AIDS Treatment News #370, August 24, 2001
phone 800-TREAT-1-2, or 215-546-3776

CONTENTS

** Liver Fibrosis in HIV/Hepatitis C Coinfection: HIV
Protease Inhibitors May Be Protective
A study to see if HIV protease inhibitors increased risk of
liver toxicity in persons coinfected with hepatitis C
unexpectedly found that they may reduce liver damage from
the disease.

** Tenofovir: FDA Hearing October 3, Public Comment
Deadlines September 26
An FDA advisory committee will hold a one-day public
hearing on this important new antiretroviral.

** Homocysteine, HIV, and Heart Disease
Too much homocysteine in the blood is associated with an
increased risk of heart and circulatory diseases. Blood
tests can detect the problem, and it can often be treated
with nutrition and supplements. Here is some background on
this potential approach to reducing cardiovascular risk.

** AIDS Treatment Activists Form New Coalition
A new treatment activist coalition, formed in mid August,
will develop national strategies, plan mentoring of new
activists, and help persons with HIV and activists find
consensus and work together on issues involving treatment
research and access to care.

** Action Alert: Global AIDS Funding
Senators especially need to hear that their constituents
care about international AIDS.

** NATAF Scholarship Deadline August 31; You Can Apply
Online
The North American AIDS Treatment Action Forum will be held
December 2-5 in Vancouver. But for those needing
scholarships, the deadline to apply for a scholarship is
now.


***** Liver Fibrosis in HIV/Hepatitis C Coinfection: HIV
Protease Inhibitors May Be Protective

by John S. James

A study of 182 patients at a major hospital in France
suggests that HIV protease inhibitors may help to reduce
liver fibrosis and cirrhosis in patients with both HIV and
hepatitis C.(1)

This study, conducted in patients with both hepatitis C and
HIV, was done to determine if protease inhibitors were
really harmful to such patients, as had been reported in
some cases. In fact, the opposite was found; use of
protease inhibitors was associated with significantly less
liver damage in this study. No one knows why, although the
authors suggested several possible mechanisms. This new
study is the first large, long-term followup of coinfected
patients which included liver biopsy data -- which may help
explain why it found different results.

The new study, published in the August 2000 HEPATOLOGY,
analyzed a cohort of patients who had been treated at the
hospital between 1995 and 2000, and on whom careful medical
records had been kept. A statistical analysis found four
independent predictors of progression to cirrhosis (severe
scarring of the liver): absence of protease inhibitor
therapy (relative risk 4.74), heavy alcohol use (greater
than or equal to 50 grams per day -- about 5 drinks a day -
- relative risk 4.71), CD4 count under 200 (relative risk
2.74), and age greater than 20 years at the time of
hepatitis C infection (relative risk 2.74).

The protective effect of antiretroviral treatment was found
only for protease inhibitors, not for nucleoside analog
drugs. (There were not enough patients treated with NNRTIs,
such as nevirapine or efavirenz, to make a comparison.)

The authors suggested that using protease inhibitors in HIV
therapy, reducing alcohol consumption, and keeping CD4
counts high might be beneficial in coinfected patients.

This study was limited because it was not a randomized
trial where patients were randomly assigned to use protease
inhibitors or not, with long-term followup with liver
biopsy. The authors noted that such as trial would be
impossible for both ethical and practical reasons.

References

1. Benhamou Y, Di Martino V, Bochet M, and others. Factors
affecting liver fibrosis in human immunodeficiency virus-
and hepatitis C virus-coinfected patients: Impact of
protease inhibitor therapy. HEPATOLOGY. August 2001; volume
34, pages 283-287.

Note

For more information on hepatitis C and coinfection with
HIV, see THE HEPATITIS REPORT by Michael Marco and Jeff
Schouten, available at http://www.treatmentactiongroup.org
(click on "HIV/HCV Coinfection").


***** Tenofovir: FDA Hearing October 3, Public Comment
Deadlines September 26

by John S. James

On October 3 the FDA's Antiviral Drugs Advisory Committee
will hold a public hearing on tenofovir (full chemical name
tenofovir disoproxil fumarate, or tenofovir DF; new brand
name Viread(TM)), an antiretroviral developed by Gilead
Sciences and currently in pre-approval expanded access.
Public comments are scheduled for the October 3 hearing,
and written statements can also be submitted. Both written
comments, and sign-up to make an oral presentation, are due
at the FDA by September 26. Details are included in the
official announcement below.

[Name and drug class: The full chemical name of tenofovir
is tenofovir disoproxil fumarate, or tenofovir DF; the new
brand name is Viread. Tenofovir is a *nucleotide* analog --
differing from the nucleoside analogs (AZT, d4T, etc.) in
that it requires less processing within cells, and
therefore is active in certain cells where the nucleoside
analogs generally are not. Both nucleotide analogs and
nucleoside analogs are reverse transcriptase inhibitors.]

On the following day, October 4, the same Advisory
Committee will discuss another drug, voriconazole, for
severe fungal infections.

Comment

Tenofovir is an important new HIV treatment because of its
resistance profile, potency, apparently low side effects,
and ease of use. The Committee is expected to recommend it
for approval. (The FDA does not have to follow the
recommendation of an Advisory Committee, but it almost
always does.)

A likely issue before the Committee will be whether to
recommend a broad indication (such as "indicated in
combination with other antiretroviral agents for the
treatment of HIV infection"), or a narrow one that would
limit the drug to advanced patients, where more data is
available. In either case physicians would legally be
permitted to prescribe the drug for any patient, but
insurance reimbursement will often be a problem if the drug
is labeled only for treatment-failure cases and physicians
want to use it earlier. We believe that approval with a
broad indication is important for several reasons:

* Tenofovir has already been shown to work well for
advanced HIV patients, the most difficult to treat. While
less information is available today for its use early in
treatment, everything we know about antiretrovirals
suggests that they work at least as well when used early in
treatment, and with at least as good a safety profile.

* Many patients cannot tolerate existing regimens because
of metabolic or other side effects. Their physicians may
want to try changing their regimen early, for example when
lipoatrophy (fat wasting) first begins to develop, to
prevent long-term harm. Even though much remains unknown
about metabolic side effects and how to manage them,
doctors and patients should have more options to try if
necessary, without having to fight HMO red tape or pay for
necessary drugs out of pocket.

* Some doctors are moving toward using stronger drug
combinations first, instead of keeping them in reserve for
when the other treatments fails -- and the patients have
become more difficult to treat. Medical opinion is still
largely unformed on this issue; no one knows for sure which
strategy is better, and in practice we will probably learn
from clinical experience before we learn from clinical
trials. Reimbursement obstacles should not block clinical
practice and experience.

* Adherence remains crucial, and is improved by regimens
that are easy to take. Tenofovir is taken as one tablet
once a day, so it can be a part of once-daily regimens,
important for patients with adherence difficulties and also
for tests of directly observed therapy.

* It has been hard to get companies to research new drugs
for advanced patients. Most prefer to test their drugs
earlier when it is usually easier to show viral-load
changes and lack of side effects. Gilead did test tenofovir
first in late-stage patients, and if it is punished with a
restrictive label, other companies will become even more
reluctant to test early for advanced patients, who need new
options the most. (Gilead is now running a large trial,
called Study 903, for treatment-naive patients, but data
will not be available until 2002.)

One can never be sure what will come out of an advisory
committee -- especially when the FDA has been under
increasing pressure in recent years to be more conservative
in its drug approvals. We hope HIV physicians will write or
speak to the Committee about their need for new treatment
options -- and tell the Committee and the FDA what labeling
for tenofovir would be best.

FDA Meeting Announcement, Distributed August 21:

The Food and Drug Administration (FDA) will hold a public
meeting of the Antiviral Drugs Advisory Committee on
October 3 and 4, 2001, 8:30 a.m. to 5 p.m. at the Town
Center Hotel, Maryland Ballroom, 8727 Colesville Road,
Silver Spring, MD. For directions, or information about
lodging, please call the hotel directly at (301) 589-5200.

On October 3, 2001, the committee will discuss new drug
application (NDA) 21-356, for Viread(TM), (tenofovir
disoproxil fumarate) Tablets, proposed for the treatment of
Human Immunodeficiency Virus (HIV) infection. The sponsor
is Gilead Sciences, Inc.

Additionally, on October 4, 2001, the committee will
discuss new drug application (NDA) 21-266, for Vfend(TM)
(voriconazole) Tablets, and (NDA) 21-267, Vfend(TM) I.V.
(voriconazole) for Infusion, Pfizer Global Research and
Development, proposed for the treatment of invasive
aspergillosis, serious Candida infections, infections
caused by Scedosporium spp. and Fusarium spp., rare and
refractory infections and empirical treatment.

This meeting is free and open to the public. No prior
registration is required to attend.

Interested persons are encouraged to present data,
information, or views, orally or in writing, on issues
pending before the committee.

If you would like to make an oral presentation, please send
the following information to: Tara Turner, Pharm.D., Center
for Drug Evaluation and Research (HFD-21), 5600 Fishers
Lane, Lane (for express delivery: 5630 Fishers Lane, rm.
1093) Rockville, MD 20857, by FAX at 301-827-6776, or by e-
mail to TurnerT@... by September 26, 2001.
* Name of speaker (and organization/affiliation if
appropriate)
* Address, phone and FAX numbers
* A brief summary statement of your comments
* Approximate amount of time you would like to speak

Oral presentations from the public are scheduled on both
days between approximately 1 p.m. and 2 p.m. Time allotted
for each presentation may be limited, depending on the
number of speakers.

Written submissions may also be sent to Dr. Turner by
September 26, 2001.

Please call the FDA Advisory Committee Information Line, 1-
800-741-8138 (301-443-0572 in the Washington, DC area),
code 12531, for up-to-date information on this meeting.


***** Homocysteine, HIV, and Heart Disease

by Jennifer E. Cohn

[Note: Abnormally high levels of homocysteine in the blood
are associated with increased risk of heart disease, and a
number of other diseases as well. These high levels can be
detected by a blood test, and are often caused by dietary
deficiencies that can be corrected.

[Reducing disease risk by controlling homocysteine level is
today considered experimental; for example, it is not part
of the new NCEP (National Cholesterol Education Program)
guidelines published May 16, 2001, probably because much of
the data is just emerging and is sometimes contradictory.
But because excessive homocysteine is strongly suspected to
be unhealthy in many ways, because it can be easily
controlled in many cases, and because vitamin B12
deficiency (which can cause excess homocysteine) is already
an important risk for persons with HIV, we believe there
should be more attention to this potential medical
strategy.

[Therefore we asked Jennifer Cohn, a medical student in
Philadelphia, to look into the literature on homocysteine
and cardiovascular risk and prepare a brief report, to help
raise awareness in the HIV community. JSJ]

* * *

Homocysteine is a non-essential amino acid; high levels
have been associated with cardiovascular disease. Excessive
homocysteine levels can be caused by a deficiency of folate
and/or vitamin B12. Deficiencies of folate can arise
because a person is not eating enough fruits and leafy
green vegetables. Vitamin B12 deficiency can occur in
vegetarians (since this vitamin is not found in plant
sources), but deficiencies are more commonly caused by poor
absorption, which can result from HIV disease, aging, and
other causes.

Excess homocysteine may have varying effects on an
individual's health. For example, increased levels of
homocysteine have been associated with both increased risk
of Alzheimer's and cardiovascular disease.(1,2)
Furthermore, some preliminary studies have demonstrated
that a certain form of homocysteine, called "reduced
homocysteine," may increase HIV viral replication.(3)
However, the literature on homocysteine levels and viral
replication is inconsistent(3, 4) -- so this article will
focus on one of the better documented effects of
homocysteine: its effect on the cardiovascular system.

Many studies of non-HIV infected individuals have shown
elevated serum homocysteine levels to be a risk factor for
vascular disease. In particular, a review article by
Boushey et al. (1995) highlighted homocysteine as a causal
factor for arteriosclerotic vascular disease.(1)
Individuals with a high level of serum homocysteine had 2.5
times the risk of developing vascular disease as those with
a normal level; this makes serum homocysteine levels a
stronger risk factor for vascular disease than serum
cholesterol. In another study, Stubbs et al. (2000)
demonstrated that for patients being admitted for acute
cardiac events, serum homocysteine levels were an excellent
predictor of later cardiac events such as another heart
attack or death from a heart attack.(5)

The mechanism by which homocysteine acts is still unclear.
However, research suggests that it affects the lining of
blood vessels.(6) Increased serum homocysteine levels may
damage this lining or make it hard for blood vessels to
relax, making it easier for arteriosclerotic plaques to
develop. Homocysteine may also change factors in blood
itself so that the blood becomes more prone to clot.(1,6)

How does homocysteine affect people with HIV?
Unfortunately, at the present time few studies are
investigating this question. However, it is probably a
reasonable assumption that homocysteine increases the risk
of vascular disease in people with HIV in the same way as
it does in people without HIV -- but if persons have
already developed other risk factors for cardiovascular
disease, high homocysteine levels may be even riskier for
them. And persons with HIV may have a more difficult time
absorbing Vitamin B12, leading to an increase in serum
homocysteine.(7)

Some drugs may also increase homocysteine levels. Examples
of such drugs include nicotinic acid (niacin), theophylline
(used for asthma, emphysema and bronchitis), methotrexate
and L-Dopa.(8)

The most important and easiest treatment is taking dietary
supplements of Vitamin B12, Vitamin B6, folic acid and TMG
(betadine), in addition to eating a balanced diet including
fruits and green leafy vegetables.(1,7) While there are
suggested daily amounts of supplements, the only reliable
way to know if a patient is taking the right amounts to
control a high serum homocysteine level is by having a
blood test for homocysteine.

References

1. Boushey CJ, Beresford SA, Omenn GS, and others. A
quantitative assessment of plasma homocysteine as a risk
factor for vascular disease: Probable benefits of
increasing folic acid intakes. JAMA. October 4, 1995;
volume 274, number 13, pages 1049-57.

2. Muller F, Svardal AM, Aukrust P, and others. Elevated
plasma concentration of reduced homocysteine in patients
with human immunodeficiency virus infection. AMERICAN
JOURNAL OF CLINICAL NUTRITION. February 1996; volume 63,
number 2, pages 242-8.

3. Simon G, Moog C and Obert G. Effects of glutathione
precursors on human immunodeficiency virus replication.
CHEMICAL BIOLOGICAL INTERACTIONS. June 1994; volume 91,
numbers 2-3, pages 217-24.

4. Balzarini J, De Clercq E, Serafinowski P, and others.
Synthesis and antiviral activity of some new S-adenosyl-L-
homocysteine derivatives. JOURNAL OF MEDICAL CHEMISTRY.
November 27, 1992; volume 35, number 24, pages 4576-83.

5. Stubbs PJ, Al-Obaidi MK, Conroy RM and others. Effect of
plasma homocysteine concentration on early and late events
in patients with acute coronary syndromes. CIRCULATION.
August 8, 2000; volume 102, number 6, pages 605-10.

6. Al-Obaidi MK, Philippou H, Stubbs PJ, and others.
Relationships between homocysteine, factor VIIa, and
thrombin generation in acute coronary syndromes.
CIRCULATION. February 1, 2000; volume 101, number 4, pages
372-7.

7. Remacha AF, Riera A, Cadafalch J and others. Vitamin B-
12 abnormalities in HIV-infected patients. EUROPEAN JOURNAL
OF HAEMATOLOGY. July 1991; volume 47, number 1, pages 60-4.

8. Cardiovascular Consultants Medical Group: Homocysteine
and the Heart, July 30, 2001,
http://www.cardiacconsultants.com/homocysteine.htm


***** AIDS Treatment Activists Form New Coalition

by John S. James

Twenty-one U.S. AIDS treatment activists met for three days
in August and began to outline a new coalition to improve
AIDS research, treatment access, and empowerment of new
activists in communities most affected by the epidemic. The
August 17-19 meeting, hosted by The Center for AIDS: Hope
and Remembrance Project in Houston, Texas, resulted from
earlier community meetings held at the annual Retroviruses
conference in 2000 and 2001.

The new organization, tentatively named AIDS Treatment
Activist Coalition, will address several concerns:

* There is no national organization or meeting of AIDS
treatment activists to discuss and develop overall
strategy. (NATAF, the North American AIDS Treatment Action
Forum, serves another purpose, educating new activists and
advocates.)

* Each year there are at least a dozen pharmaceutical
company meetings with AIDS treatment activists. These
meetings are called by different companies, each of which
sets the agenda and decides who will be invited to
represent patients and the public. U.S. activists want to
move toward the European system of ongoing, structured
meetings with the companies, where the community selects
its own representatives and invites the company whose
products will be discussed, instead of letting industry
determine who will represent the community at major
company/community meetings. ATAC also hopes to improve
communication about the discussions that take place at
these meetings, so that activists who do not attend can be
informed.

* Treatment activists must be more representative of the
demographics of the epidemic (including more people of
color, women, and young people). The new organization will
emphasize mentoring, educating, and empowering new
activists -- and may require members to recruit others from
underrepresented groups.

* Today a small number of highly experienced activists are
overcommitted. We need to help provide more opportunities
for treatment education, and otherwise make it feasible for
more people to become treatment activists.

ATAC will focus on biomedical research, including
diagnostics, vaccines and microbicides as well as drugs,
and will include AIDS-related illnesses such as hepatitis C
and tuberculosis, as well as HIV infection and its
complications.

Membership policies, bylaws, and other specifics are still
being determined. For example, it is likely that membership
will be open to all persons with HIV and their advocates,
with members joining as individuals (not as representatives
of organizations) and paying nominal dues; but there might
or might not also be a separate category of organizational
member for nonprofit organizations. The organizers are
seeking input from the public and can be reached through
the email addresses below.

Standing committees so far are Bylaws; Communication;
Fundraising; Membership; Mentoring; and Research,
Development, and Access.

For More Information; Contacting ATAC

ATAC has started a Web site at http://www.atac-usa.org; you
can also send email to info@...

ATAC has a temporary steering committee, and you can also
contact the members individually:
Parrish Crosby Parrishfc@...
Yvette Delph YvetteDelph@...
Larry Diaz sadatatx@...
Mike Donnelly MrDonnelly@...
Gregg Gonsalves greggg@...
Michael Marco Mikemarco@...
Bob Munk bobmunk@...
Claire Rappoport clairer@...

Notes:

(1) This writer participated in the organizing meeting in
Houston, and drafted the statement above with the
assistance and approval of the group.

(2) We are especially impressed that this coalition has
started useful work immediately, within a week of its
organizing meeting; see http://www.atac-usa.org


***** Action Alert: Global AIDS Funding

by John S. James

It is especially important now for U.S. citizens to let
their two Senators know they are concerned about funding to
control AIDS and other infectious diseases around the
world. The Democrats have been worse on this issue than the
Republicans -- not because they are opposed, but because
they do not think people care. Calls before Labor Day are
most important. But it never hurts to let Congress know
that their constituents care about AIDS in Africa and
elsewhere, and infectious diseases everywhere.

Background

An August 20 alert from the Treatment Action Network of
Project Inform summarizes the situation:

"On April 26th, 2001, United Nations Secretary General Kofi
Annan launched the 'Global AIDS and Health Fund'. This
international fund is intended to treat and prevent
HIV/AIDS, tuberculosis, and malaria for those without
access to medicine, health care, and prevention programs.

"This spring, President Bush pledged a $200 million
contribution to this fund. While a small step forward, this
amount falls well short of the $2 billion asked of the
United States and lowered the bar for other contributors.
Major donors have scaled back their contributions and the
momentum has slowed. Advocates have turned to Congress to
increase this pledge.

"While the process hasn't finished in the House of
Representatives or the Senate, it appears that the House
will approve about the same amount as the President has
pledged. It is critical that the Senate propose a much
larger amount. The House and Senate will have to meet to
negotiate a final amount to send to the President for
approval. To prepare for these negotiations, it is crucial
that the Senate come to the table with a large number,
rather than the smallest!

"Constituent pressure is essential to ensure that elected
officials make the global AIDS crisis a priority. If
everyone who cares about the international AIDS epidemic
meets with, calls, or writes a letter to their Senators
this month, we could have a major impact in focusing their
attention on this issue. Please take a few minutes to
respond to this Alert!

... "You can find contact information for your two U.S.
Senators by accessing their individual websites through the
main U.S. Senate website. Go to http://www.senate.gov, then
click "List Senators By State". You'll find links to both
of your Senators underneath your state. Each website will
have Washington and district phone, fax, and mailing
addresses."

Notes:

(1) It is best to avoid email to political offices unless
you know that they are prepared to include email in their
counts of public opinion on issues. If you do email your
Senators, include your street address so they will know it
is coming from a constituent. You might call their office
and ask if email is a good way to communicate with them --
or if you should write or call instead.

(2) This alert is intended for the month of August (before
Labor Day). But it is never too late to let your
representatives know that you care about AIDS in Africa and
elsewhere, and infectious diseases throughout the world.

Doing our part to control epidemics is entirely feasible
and is the right thing to do, and it makes us all safer in
an increasingly populated, mobile, and interconnected
world.


***** NATAF Scholarship Deadline August 31; You Can Apply
Online

"The 2001 North American AIDS Treatment Action Forum
(NATAF) will be held December 2-5 at the Sheraton Vancouver
Wall Centre Hotel, Vancouver, Canada. The forum is designed
to educate individuals interested in becoming HIV/AIDS
advocates and educators; to enhance their skills and
knowledge; and to develop inclusive, national strategies to
ensure the continuity and success of the treatment advocacy
movement.

"NATAF 2001 is open to anyone interested in broadening
their knowledge of HIV/AIDS research and treatment issues,
and learning to use this knowledge to advocate on behalf of
everyone living with HIV/AIDS. Participants include the
volunteers, staff, and board members of community-based
organizations, case managers, social workers, AIDS
educators and outreach workers, pharmaceutical and
government representatives, healthcare professionals and
people living with HIV/AIDS.

"Scholarships Deadline August 31st: Deadline for
scholarships application is 6:00 PM (Eastern) on August 31,
2001. For information about scholarships or to apply
online, please go to
http://www.nmac.org/nataf/2001/scholarship/scholarship.htm

Note:

Project Inform included the following to it's Treatment
Action Network (tan@...) "While many of the
questions on the scholarship form ask about your agency,
applications are especially encouraged from individuals not
association with an agency or organization. Put "N/A" on
the agency questions and focus on the personal statement
section."


***** AIDS TREATMENT NEWS

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AIDS Treatment News
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