Report to the Community: Steering Committee on the Metabolic Complications of HAART

[Guest guest]

Dear colleagues:

Attached is a summary report from meetings of the Steering Committee

on the Metabolic Complications of HAART held in New York on 5th and

6th November together with a Position Paper from the D:A:D Study. It

was prepared by the community representatives: Bob Munk,

Learned, and Simon . The first day was devoted to follow-up

and discussion of the Committee's initial mandate, which was to

examine the relationship between HAART and cardiovascular events. The

second day included Committee members as well as experts in liver

disease as part of a newly-formed Liver Toxicity Working Group.

Any questions, comments or suggestions can be sent to the community

representatives on the Committee:

Simon , HIV i-Base, London, simon.collins@...

Learned, AIDS Community Research Initiative of America (ACRIA),

jlearned@...

Bob Munk, New Mexico AIDS InfoNet, bobmunk@...

Steering Committee on the Metabolic Complications of HAART: Report to

the community

The following is a summary report from the HAART Oversight Committee

meetings held in New York on 5th and 6th November. It was prepared by

the community representatives: Bob Munk, Learned, and Simon

. The first day was devoted to follow-up and discussion of the

Committee's initial mandate, which was to examine the relationship

between HAART and cardiovascular events. The second day included

Committee members as well as experts in liver disease as part of a

newly-formed Liver Toxicity Working Group.

Background

Four years ago, the Committee for Proprietary Medicinal Products

(CPMP) of the European Agency for the Evaluation of Medicinal

Products (EMEA), Europe's regulatory agency, mandated the

pharmaceutical companies that were then marketing protease inhibitors

to work together to look at the extent of risk of cardiovascular

events related to lipodystrophy.

This was due to concern that lipodystrophy and lipid increases could

lead to higher rates of heart disease, and that the risk might be

sufficiently high to change recommendations for the use of HAART.

The Steering Committee on the Metabolic Complications of HAART was

set up to commission and fund independent research to answer these

outstanding questions. Its membership includes the manufacturers of

all HIV antiretrovirals (primarily representatives from the

medical/clinical rather than the marketing side) and has most

recently expanded to include Gilead Sciences. The Committee is

co-chaired by Professor Ian Weller (Academic/Independent) and

Pizzuti (Bristol-Myers Squibb). It includes representatives from each

company, community representatives from the European AIDS Treatment

Group (EATG) and from the US, and representatives from the EMEA

(Orjan Mortimer) and the Food and Drug Administration (FDA) (Jeff

Murray).

Several major studies of lipodystrophy and its relation to

cardiovascular disease have been sponsored and results have been

published in leading journals. Two of these studies are still

ongoing.

Study results on lipodystrophy and cardiovascular risk

From a patient perspective, it has been extremely important that a

regulatory agency has been able to facilitate important collaborative

research between companies on post-marketing safety studies. Broadly

speaking, it has recognised that all the companies have a shared

interest and responsibility for things that cannot necessarily be

pinned down to their individual products. Importantly, this research

is paid for jointly by the companies, although once commissioned the

research is undertaken by independent investigators. The studies

commissioned by the Committee include:

… A study to develop an objective definition of lipodystrophy.

Principal investigator: Carr. Study completed and published.

… A retrospective study of the Veterans Administration database to

review rates of cardiovascular disease. Principal investigator: Sam

Bozzette. Initial phase of study completed and published.

… A prospective study of cardiovascular disease rates in patients

included in several cohorts, primarily in Europe, the D:A:D study.

Over 30,000 patients total. Principal investigator: Jens Lundgren.

Initial phase of study completed and published.

… A meta-analysis of large trials that compare metabolic parameters

for patients on regimens including protease inhibitors to those

including non-nucleoside reverse transcriptase inhibitors. This

analysis must wait for the completion of the studies to be analysed,

which will not occur for a few more years.

Much of this research is continuing. A first analysis from the Data

Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study showed

an increased relative rate of heart disease with each year of use of

combination therapy. However the absolute risk for individual

patients is generally very small - because the starting risk for most

patients is also low. The benefits of HAART are still much greater

than any small increase risk of heart disease. However, the

importance of modifiable factors, such as stopping smoking, taking

exercise, diet changes and use of lipid-lowering drugs where

appropriate should be recognised as being as important for

HIV-positive people as for the general population.

The D:A:D study recently released a Position Paper (attached) that

puts the risk of cardiovascular disease into the context of overall

HIV antiviral treatment. Ongoing research is looking in more detail

at the results and continuing the research over a longer period.

The Committee is considering plans to " refresh " the D:A:D cohorts to

include some patients on newer regimens and reflecting more current

practices on treatment of cardiovascular risks.

The Committee is also considering proposals to extend and refine some

of the analysis of the Veterans Administration database.

Liver Toxicity Working Group Meeting

More recently, the Committee was asked by the EMEA to explore changes

in the use of their products that might be required for patients with

liver impairment. The initial request from the EMEA to the companies

raised the issue in very broad terms, concluding 'there is a

disturbing lack of general and product specific knowledge'. It asked

them to come up with a response to the lack of safety data in this

area. In May 2003, the FDA also issued a " Guidance for Industry "

concerning what it would like to see in terms of study designs and

data on pharmacokinetics in patients with impaired hepatic function.

The Committee is now looking broadly at liver impairment and how best

to define and identify it. The discussion was informed by

presentations from several leading hepatologists (Yves Benhamou,

Massimo Puoti, and Dieterich). With the help of everyone in

attendance, progress was made toward a standard definition, although

there is not yet any formal plan on how to proceed.

The participating companies will review their existing clinical

trials data and may consider sponsoring new research to find out the

relationship between the effects of individual drugs in people with

coinfection with viral hepatitis (HBV/HIV and HCV/HIV) and other

liver disease. The urgency for this research is that clinical trials

of HIV drugs are conducted largely in patients who do not have

coinfection, and yet, once approved, they are widely used by people

with coinfection. Approximately 10% of HIV-positive people in Europe

are coinfected with hepatitis B and 20-50% are coinfected with

hepatitis C (depending on region). In the United States, the number

of HIV-positive people coinfected with hepatitis B is closer to 25%

and the number of HIV-positive people coinfected with hepatitis C is

approximately 25-30% (also depending on region).

One result from more intense investigation of toxicity associated

with nevirapine (Viramune) presented at the Committee meeting on

November 6, 2003, was that the risk of rash-associated liver toxicity

is significantly connected with starting treatment with CD4

count >250 cells/mm3 for women and >400 cells/mm3 for men. These

results will be reflected in the prescribing information for

nevirapine.

We welcome and support this collaborative activity and additional

research. The EMEA and the FDA have been clear about the importance

of addressing the lack of data in coinfected patients. We strongly

support the members of the Committee in jointly developing a

definition of hepatotoxicity, and collaborating in the development

plans that will generate the best possible data from existing cohorts

and company databases.

Further information

Any questions, comments or suggestions for issues to be addressed can

be sent to the community representatives on the Committee:

Simon , HIV i-Base, London, simon.collins@...

Learned, AIDS Community Research Initiative of America (ACRIA),

jlearned@...

Bob Munk, New Mexico AIDS InfoNet, bobmunk@...