AIDS TREATMENT NEWS Issue #372, October 19, 2001
phone 800-TREAT-1-2, or 215-546-3776

CONTENTS

** Tenofovir: FDA Hearing on Important New Antiretroviral
Report on the FDA advisory committee hearing on tenofovir
(Viread(TM)), a new antiretroviral about to be approved.

** Apparently Harmless Virus Associated with Reduced HIV
Death
Infection with a virus that does not cause any known
disease has been associated with a much better survival
rate in persons with HIV. The mechanism of action is
unknown. With further research, this finding might lead to
a new class of drugs to help control HIV.

** Retroviruses Conference: Major Deadlines Nov. 16
Anyone going to the Retroviruses conference next February
either as community press or through the community
scholarship program must apply by November 16. Applications
from developing-country researchers and clinicians applying
for international scholarships are also due on that date.

** Barcelona International Conference, July 7-12, 2002:
Time to Start Planning
Early applicants can get more convenient housing and a
reduced admission price, and many international tickets go
on sale early in the year.

** "A Day for Women" Medical Information Meeting, November
3 in New York
A one-day meeting on women's HIV treatment issues will
allow participants to ask questions of the experts. The
meeting is free, but registration is required due to
limited space.

** New HIV Drugs: Extensive Lists, Additional Information
Here are links to lists of HIV drugs in development, and to
an article about some of the most important ones.

** Africa Access News
Much is happening in the fight for access to treatment in
developing countries, especially countries in sub-Saharan
Africa.


***** Tenofovir: FDA Hearing on Important New
Antiretroviral

by John S. James

The FDA's one-day public hearing on tenofovir (brand name
Viread(TM)), a new antiretroviral being developed by Gilead
Sciences, took place October 3 near Washington D.C. (see
AIDS TREATMENT NEWS # 370, August 24, 2001). This meeting
of the Antiviral Drugs Advisory Committee (a group of
outside experts convened by the FDA) also included
consultants selected for this particular meeting because of
their special expertise.

Everyone who spoke agreed that tenofovir should be
approved; the FDA had no issue with approval, which is
expected shortly. In clinical trials the drug has shown a
0.6 log decrease sustained for the length of the trial (up
to a year so far), when added to an antiretroviral regimen
which was failing to suppress the virus -- a difficult test
for a drug, and probably not the way tenofovir will
generally be used. (Usually at least some of the other
drugs in the regimen would be changed, often after
resistance testing -- although it is too early to know for
sure how tenofovir will be used in practice.) Resistance to
tenofovir seems slow to develop, although resistant viruses
do occur. The drug is easy to use (it is taken only once a
day, with food), and so far has shown excellent safety in
human tests, with side effects comparable to those reported
by volunteers who received the placebo.

One major issue at the hearing was whether the FDA should
recommend tenofovir for combination use in HIV treatment
for any patient -- including those starting antiretrovirals
for the first time -- or only recommend it for advanced
patients, where there is currently more data. All activists
who spoke wanted the general indication, but for a variety
of reasons the committee tended toward the more restrictive
one (there was no formal vote). Activists want to free
doctors and patients from possible reimbursement hassles if
they decide to use the drug in front-line therapy; they
also wanted to make sure the company was not punished for
testing tenofovir first in advanced patients, which
activists and the FDA have urged companies to do, since
these patients most need new options.

But committee members were concerned that less is known
about first-line use and more will be known next year, when
the indication could be changed. Some felt that the lack of
complete information about first-regimen use changed the
risk/benefit ratio of using a new combination vs. a
standard one. Others noted that ADAPs (the AIDS Drug
Assistance Programs, run separately by each state) are
unlikely to micromanage patients, so they will not deny
reimbursement if a physician uses the drug outside of the
indications formally approved by the FDA. Some saw the
drug's indication as mainly a marketing issue. (Doctors are
free to prescribe an approved drug for any patient, without
being bound by the indications.)

Some observers think the FDA may approve the general
indication but with a note saying that studies in
treatment-naive patients are not yet complete.

Long-Term Safety Issues

Human safety data were very good -- in particular, there
was none of the kidney toxicity that had been seen in
adefovir when studied for HIV at doses of 60 and 120 mg
daily. (Adefovir, a much less effective antiretroviral in
the same drug class as tenofovir, is no longer being
developed for HIV, but is a promising potential treatment
for hepatitis B, in much smaller doses.)

But animal studies using tenofovir doses much higher than
those given to people had found a bone problem,
osteomalacia -- a lack of normal mineralization of the bone
(this disease is called rickets in children, osteomalacia
in adults). While the danger appears to be low -- the
condition can be treated, and reversed completely in
animals when the drug was stopped -- two bone experts
brought by the FDA as consultants to the committee thought
that certain steps should be taken now in order to head off
possible problems in the future:

(1) Gilead should do some simple research to find out which
potential mechanism caused the problem in the animals. Was
bone failing to mineralize properly because of a deficiency
of the minerals in the body? Or was the drug interfering
with enzymes involved in the mineralization process? The
company might be able to learn much by analyzing samples
already in its freezers.

(2) The bone specialists recommended that certain baseline
tests be done before tenofovir is started -- at least to
look for vitamin D deficiency and certain other simple
nutritional problems that could easily be corrected with
nutritional supplements or other treatments. One of the
consultants listed baseline studies he would ideally like
to do today -- probably too many to be feasible for
widespread clinical practice -- but noted that once the
mechanism studies had been done, much of that baseline
testing could become unnecessary. Pregnant women and
children could be at particular risk for any bone
mineralization problem.

We left the hearing with the impression that this issue
should not delay approval of tenofovir -- the drug is
needed now, and the bone risks are not immediate if they
exist at all. But the discussion pointed out the need for
biochemical research on the mechanism of the bone changes
in animals, and strongly suggested at least some baseline
testing when the drug is started, for correction of
relevant nutritional deficiencies if necessary.

(According to Gilead, much of this work had already been
done but was not presented at the hearing because the FDA
was already comfortable with the data. And bone markers are
now being measured in study 903, a clinical trial of
tenofovir in treatment-naive patients.)

Other Possibilities

Tenofovir may have other important uses than the HIV
treatment for which it will be approved:

* Hepatitis B. Tenofovir may prove to be an effective
hepatitis B treatment. One activist urged that this use be
planned for in co-infected people, instead of left to
chance, so that the hepatitis B as well as HIV treatment
could be optimized, to reduce the risk of patients
developing tenofovir-resistant hepatitis B.

* Mother-to-infant transmission. One committee member noted
theoretical reasons why this drug might be effective. If so
it would have an advantage over nevirapine, in that
resistance to tenofovir is much slower to develop. [We
would also like to know if adding a single dose or very
short course of tenofovir to the single dose of nevirapine
could make the regimen more effective in preventing
maternal transmission -- a possibility which would seem to
be quite feasible to test, because of the safety of
tenofovir, the fact that nevirapine is far from 100%
effective (allowing a better regimen to be detected), and
the fact that everyone in the trial would get at least the
accepted nevirapine regimen.]

* Microbicide use? PMPA, the active form of tenofovir,
proved very effective in preventing HIV infection in early
animal studies (tenofovir is a chemical modification of
PMPA, designed so that the drug could be given orally, as
PMPA cannot). We do not recall microbicide possibilities
coming up at this hearing, which had a different focus; but
PMPA is now being studied by the U.S. National Institute of
Allergy and Infectious Diseases as a possible vaginal
microbicide. An effective microbicide would have a great
impact on the global HIV epidemic because it would provide
a prevention method controlled by women.

For More Information

A summary and a transcript will be on the FDA Web site, at:
http://www.fda.gov/ohrms/dockets/ac/acmenu.htm (click on
'2001', then 'Anti-Viral Drugs Advisory Committee').

Usually the transcript is available 30 days after the
meeting, the summary approximately 90 days after. Some
other information about the October 3 meeting is already on
this site.


***** Apparently Harmless Virus Associated with Reduced HIV
Death

by John S. James

Two independent studies published September 6, 2001, in the
NEW ENGLAND JOURNAL OF MEDICINE(1,2) found that persons
with HIV who were also infected with a virus not known to
cause disease had a much lower death rate than those who
were not infected -- with the risk of death being reduced
about two to four times, depending on how the comparisons
were done. The mechanism of this effect is not known,
although there are some hints from laboratory studies. An
accompanying editorial includes a warning against attempts
to infect people deliberately, at least until more is
known(3).

The finding is not new; five early studies had reported a
similar result, and one had failed to find it (that study
was done differently); for references, see the Discussion
section of the September 6 Tillmann paper(2).

The virus, called GB virus C, is fairly common; it is found
in about 1.8% of healthy blood donors, 15% of persons
positive for hepatitis C, and up to 35% of persons with
HIV(3). This virus was first found in 1995, and is
sometimes called hepatitis G virus, but that name is used
infrequently since the virus does not appear to cause
hepatitis or any other disease. Most people infected with
GB virus C clear the infection normally; then they have
antibodies, but no live virus can be found. Persons who
have cleared the infection seem to have a somewhat reduced
death rate from HIV, but not as much protection as those
whose GB virus C infection is still active.

Comment

The importance of this finding is that it offers a window
to a possible new understanding of HIV and a new way of
controlling it.

HIV not only develops resistance to most drugs fairly
rapidly; it also seems to evolve similarly to get around
the patient's immune system. But GB virus C infection is
associated with lower viral loads and improved survival
even years later (although it is probably not associated
with higher T-cell counts). If this virus is causing these
effects, it is doing so in some way that HIV cannot easily
evolve around.

Perhaps there is no causal relationship, and GB virus C
infection gives no benefit but is only a marker for
something already in the patient that is responsible for
the better outcome. Even in this case there would still be
an unknown mechanism in the patient that is not easy for
HIV to evolve around, and that might be exploited to
develop a new kind of drug treatment -- one probably closer
to immune-based therapy than to traditional
antiretrovirals.

The hardest kind of clinical trial to conduct is one that
shows a survival benefit. Here we already have a clear
survival benefit -- and thousands of patients who could be
studied with nothing more intrusive than a blood draw.

References

1.Xiang J, Wunschmann W, Diekema DJ, and others. Effect of
coinfection with GB virus C on survival among patients with
HIV infection. NEW ENGLAND JOURNAL OF MEDICINE. September
6, 2001; volume 345, number 10, pages 707-714.

2. Tillmann HL, Heiken H, Knapik-Botor A, and others.
Infection with GB virus C and reduced mortality among HIV-
infected patients. NEW ENGLAND JOURNAL OF MEDICINE.
September 6, 2001; volume 345, number 10, pages 715-724.

3. Stosor V. and Wolinsky S. GB virus C and mortality from
HIV infection. NEW ENGLAND JOURNAL OF MEDICINE. September
6, 2001; volume 345, number 10, pages 761-762.


***** Retroviruses Conference: Major Deadlines Nov. 16

The important 9th Conference on Retroviruses and
Opportunistic Infections will take place February 24-28,
2002, at the Washington State Convention and Trade Center
in Seattle, Washington. This conference has always been
full, and this year will be limited to 3,800. Registration
is also limited to certain categories of people. Important
deadlines for "community" participation, as well as
international scholarships, are November 16. Researchers
and clinicians have other deadlines.

These applications must be received by November 16:

* Community scholarships -- Applicants must meet certain
conditions, and provide an appropriate letter of support.
See complete information on the conference Web site, below

* Community press -- AIDS newsletters, etc. must register
by November 16. See information on the conference Web site
as to how to do so. It may be difficult to be accepted if
one's publication is not already known to the conference.

* International scholarships -- "Researchers and clinicians
from developing countries working in the area of AIDS
research who, without financial support, would be unable to
participate in the conference" must apply for these
scholarships by November 16.

After being accepted applicants must meet other deadlines
to register for the conference and for housing.

If you want to go to the conference, be sure to check the
Web to confirm this information and to learn how to apply.
The conference Web site is:
http://www.retroconference.org/2002/

The Retrovirus Conference Secretariat is: Westover
Management Group, Inc., 115 South Saint Asaph St.,
Alexandria, VA 22314, 703-535-6862, fax 703-535-6899, email
info@....


***** Barcelona International Conference, July 7-12, 2002:
Time to Start Planning

The XIV International AIDS Conference will take place in
Barcelona, Spain, July 7-12, 2002; this conference meets in
different countries every even-numbered year. While not
difficult to get into, the International Conference is
expensive except for media (due to frills which developed
early and have resisted protests since -- protests
especially strong last time, in Durban, South Africa). It
helps to register early in order to get housing closer to
the meeting and minimize the daily travel time to get to
one's hotel room and back. And early registration costs
less: $850 before February 1, $950 February 1 and before
May 1, and $1050 starting May 1, with a much lower rate for
students. Note that international airfares typically go on
sale early in the year.

For information about this conference see
http://www.aids2002.com

Comment

While we certainly agree that the cost of the international
AIDS conferences needs to be lowered, we think that what is
most important is to improve the use of online
communication throughout the year -- allowing education and
collaboration around the world at far less expense than
attending any international conference. Then the
conferences could focus more on facilitating working
groups, and less on lectures in auditoriums.


***** "A Day for Women" Medical Information Meeting,
November 3 in New York

The 2nd annual women's conference by NATAP (National AIDS
Treatment Advocacy Project) will take place Saturday
November 3, 9:30 a.m. to 4:00 p.m. at the New York
University Medical Center, Auditorium E & F, 401 East 30th
St (between 1st Avenue and FDR Drive). There is no charge,
but preregistration is required and seating is limited. To
register, call NATAP at 212-219-0106, or 888-26-NATAP. You
are requested to enter at 550 1st Avenue and bring valid
photo ID.

Speakers include Judith Currier, M.D., on women's
complications, lipodystrophy, and vaccines; Janet Mitchell,
M.D., on GYN and women's infections and care; Kathleen
Squires, M.D., on women's HIV treatment, epidemiology, and
natural history, and Valerie Stone, M.D., on HIV treatment
and adherence. There will be morning and afternoon breakout
sessions for questions and answers.

For more information, call NATAP at 212-219-0109 between
10am - 6pm, Monday thru Friday.


***** New HIV Drugs: Extensive List, Additional Information

The most complete recent list we have seen of anti-HIV
drugs in development -- over 60 total, including the
approved drugs -- was posted recently by Ben Cheng of
Project Inform, on the Web site of the new AIDS Treatment
Activist Coalition.

The list, at
http://www.atac-usa.org/RDACommittee.html (scroll down, or
click on "Chart on drugs in development", has the generic
or chemical name of each compound, the class of drug
(nucleoside analog, protease inhibitor, etc.), the phase of
development (preclinical, phase I, phase II, phase III, or
approved), and the pharmaceutical company doing the work.

For another extensive list of drugs in (or formerly in)
development, see the Treatment Action Group (TAG) Web site:
http://www.aidsinfonyc.org/tag/science/pipeline.html

For more information about some of the more prominent new
drugs currently being researched, see "New Agents for Anti-
HIV Therapy," by Joseph J. Eron Jr., M.D., and Robert L.
Murphy, M.D. It is available on the Medscape site,
http://hiv.medscape.com (click on 'New Agents for Anti-HIV
Therapy' if this link is still there, or search the site
for the author's last name, and look for the title in the
results returned). Note: The Medscape site requires
registration, but registration is free, and it need be done
only once (provided you remember the user ID and password
you choose). Most articles on continuing-education medical
sites remain online for one year.


***** Africa Access News
by John S. James

** Online Petition Through November 2

See note at the end of this article.

** Huge Mining Company Says It Cannot Treat Low-Income
Workers

According to an October 9 article in the FINANCIAL TIMES,
the London-based company Anglo American decided it could
not provide antiretroviral treatment to most of its
employees in South Africa. Only about 14,000 senior staff
will be eligible for the AIDS medicines. The company
employs about 160,000 people in Africa, most of them in
South Africa -- where about 21% of the employees have HIV.

"The saving you achieve can be substantial, but we really
don't know how it will stack up," said one official. "We
feel that the cost will be greater than the saving." The
company said it would need funding from international donor
agencies to distribute AIDS treatment further.

The National Union of Mineworkers (South Africa) called the
policy "inherently racist and discriminatory, with
beneficiaries of the scheme being, in the main, white
workers and the black elite. The foot soldiers who generate
wealth in the bowels of the earth are excluded."

**South Africa: Glaxo Offers Voluntary License on AZT/3TC

On October 7 GlaxoSmithKline said it would grant a
voluntary license to Aspen Pharmacare, South Africa's
largest generic drug company, to manufacture and sell AZT
and 3TC -- a move sought by activists as well as by Aspen.
Apparently this license will only allow the drug to be sold
to government and NGO (nonprofit) organizations in South
Africa -- not in other African countries. Glaxo will charge
a royalty of 30% of net sales, which will be donated to
nonprofits fighting AIDS in the country.

The final price of the Aspen drugs is not known but is
widely expected to be much higher than prices available
from generic manufacturers in India; however, the agreement
will avoid legal obstacles that have kept the Indian drugs
out of the South Africa. (India has patent laws designed to
encourage pharmaceutical manufacturers to compete in low-
cost production methods -- a system which has worked very
well in providing low-cost medicines for that country, but
now may have to be ended because of the World Trade
Organization treaty, which requires all countries to adopt
a U.S./European patent system even for domestic drug
production.)

Note: In a separate announcement on October 3, not related
to AIDS, GlaxoSmithKline offered discounts averaging 30%
for U.S. elderly persons with limited income and without
prescription coverage. Those who qualify must be 65 or
older, and with income no greater than 300% of the federal
poverty level (which today means less than $26,000 for
individuals and $35,000 for couples). Qualifying persons
will receive a card which they will present at pharmacies.
Other companies may be under pressure to match these
discounts, since otherwise their products will now become
more expensive than competing Glaxo products for the
eligible patients.

** Generic Company Charges Patent Abuse in South Africa

On or around October 7, a South African affiliate of Cipla,
the Indian generic pharmaceutical company, filed legal
action in South Africa, accusing GlaxoSmithKline and
Boehringer Ingelheim, the maker of nevirapine, of abusing
their patents to keep prices high.

The action, described by observers as "legally
groundbreaking" and "a major move," could potentially open
the door to South African sales of HIV medications at
prices much lower than those which will result from the
voluntary licensing agreement announced the same day.

Note: For a legal analysis arguing that South Africa is
permitted under international trade rules to take "certain
legal steps to ensure meaningful reductions in drug
prices," see TRIPPING OVER PATENTS: AIDS, ACCESS TO
TREATMENT AND THE MANUFACTURING OF SCARCITY, by Jonathan
Michael Berger, University of Toronto. It can be downloaded
from:
www.tac.org.za/archive.htm (go to Research Papers).

Also on international patents (although perhaps not
relevant to this South African case) note PATENT POLITICS,
by Michael H. Davis, Cleveland State University College of
Law. Davis argues that the "ordinary practitioner" test of
nonobviousness, which determines that some patents are
granted and some are not, is inherently subjective,
allowing patent laws to implement national industrial
policy without democratic oversight -- and also making
patent law not rationally transferable across national
borders. The abstract and link to the full article are
available through the Social Science Research Network, at:

http://papers.ssrn.com/sol3/cf_dev/AbsByAuth.cfm?per_id=230701


** UN Secretary General, Pharmaceutical Companies Issue
Joint Statement

On October 5 United Nations Secretary General and
executives of seven major pharmaceutical companies met and
issued an 8-point joint statement on access to treatment.
It is at:
http://www.un.org/News/Press/docs/2001/sgsm7982.doc.htm

Comment: we find it good as far as it goes -- though it
does not go very far.

** South Africa: Major Conflict Over Death Report

A report by the Medical Research Council (South Africa's
government medical-research institution, like the U.S.
National Institutes of Health) found that AIDS had become
the largest single cause of death in the country, and that
40% of the deaths last year of South Africans age 15-49
were AIDS related. The South African government under
President Thabo Mbeki -- which has refused to provide
antiretroviral treatment through the public health system,
even for prevention of mother-to-infant transmission --
refused to release the report, which was leaked to the
press.

The report also predicted that in 10 years AIDS in South
Africa would cause more than double the deaths of all other
causes combined, and that life expectancy in the country
would drop from 54 years to 41.

On October 16, after extensive protests over its
suppression, the report was released at:
http://www.mrc.ac.za

On October 17 the Guardian (UK) covered the controversy:
http://www.guardian.co.uk/Archive/Article/0,4273,4278717,00.html

** UK Poll Shows Strong Support for Dual Pricing

On October 8 the British charity Voluntary Service Overseas
released a survey showing that 87% of people who responded
thought it was right for people with HIV in poor countries
to pay less for the medicines than people in the UK,
according to THE GUARDIAN, UK, October 8.

We do not know of a similar U.S. poll, but almost certainly
a large majority here would agree.

** For More Information

For more information on treatment access in Africa, see the
Web site of the Treatment Action Campaign (TAC), the
leading AIDS treatment activist group in South Africa, at
http://www.tac.org.za/

** Action Alert: Online Petition on Drug Patent Rules Open
Until November 2

A petition by Oxfam America, "The World Demands Fairer
Rules on Patents," is open for signatures at the Oxfam
America site:
http://www.oxfamamerica.org/petition/petition.html

Or you can sign at the Global Treatment Access site:
http://www.globaltreatmentaccess.org

The complete text of the petition is:
"14 million people in the developing world die every year
from treatable diseases, including HIV/AIDS, malaria, and
tuberculosis. The high cost of medicines is a key factor.
World Trade Organization patent rules are pushing up the
price of these medicines. I urge WTO members, in particular
the United States, to demonstrate their commitment to put
health before wealth by changing and clarifying the global
patent rules at the forthcoming WTO summit conference."

Note: The reference to the WTO summit is to the Ministerial
Conference of the World Trade Organization (WTO), which
occurs every two years; the last meeting was in Seattle in
1999. The next meeting is scheduled for November 9-13 in
Doha, Qatar, but might be moved to Singapore for security
reasons.

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AIDS Treatment News
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