Zerit letter to the FDA from ATAC

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August 28, 2003

S. Fauci, MD & G. Bartlett, MD

Co-Chairs, DHHS Guidelines Panel for the Use of Antiviral

Agents in HIV-Infected Adults and Adolescents

NIAID/NIH, Bldg. 31/Rm 7A-03

Bethesda, MD 20892

RE: Preferred First Line Recommendation of Stavudine Combination Therapy

Dear Drs. Fauci and Bartlett:

The AIDS Treatment Activists Coalition (ATAC) is a national coalition of AIDS activists, many living with HIV/AIDS, working together to end the AIDS epidemic by advancing research on HIV/AIDS and broadening access to treatment. ATAC's Drug Development Committee (DDC) works with government, academia and the pharmaceutical industry to provide a community perspective into the development of new anti-HIV drugs and the utilization of anti-HIV therapies.

We are writing to express an important community concern with respect to the July 14, 2003 DHHS Treatment Guidelines update. Namely, the generally unqualified placement of stavudine (Zerit, d4T) within a preferred first-line combination regimen despite numerous studies that associate stavudine with a variety of serious side effects -- in particular, irreversible facial lipoatrophy, which causes significant quality-of-life and adherence issues for many patients. Although a few studies have shown that switching from stavudine to abacavir may reverse limb lipoatrophy by a small amount after 48 weeks, no reversal of facial wasting was observed in these studies. There are no FDA approved and reimbursable treatments for facial wasting; and, the ones available through IDE protocols or off-label access cost over $4,500 per patient. We believe it is therefore imperative that treatment-naïve patients be informed of this significant risk if they include stavudine in their first regimen.

In contrast to the DHHS Guidelines, we cite the British HIV Association Guidelines, which provide this advice regarding stavudine: "For initial therapy, combinations including d4T are not recommended because of evidence of its role in the development of lipodystrophy and abnormal lipid profiles." While this language is simple and straightforward, the July 14, 2003 DHHS Treatment Guidelines regarding stavudine is often confusing and inconsistent. Stavudine is categorized as a preferred first line combination with lamivudine (3TC) and Kaletra, with an A I rating for strength of evidence. However, in the separate discussion of NRTI pairs, the combination of lamivudine and stavudine is referred to as an alternative (A II). Only in the next to the last sentence of the section is this deeply buried caution found: "The combination of stavudine with lamivudine is also widely used but may be more frequently associated with dyslipidemia, lipoatrophy, and mitochondrial toxicities."

Stavudine is also listed among recommended triple combinations presented in Table 12a. Only the first instance of stavudine in the NNRTI, but not the PI section of Table 12a, receives an asterisk to a footnote about an increased incidence of lipodystrophy with this drug: "*Preliminary 96-week data comparing stavudine + lamivudine vs tenofovir - lamivudine revealed higher incidence of lipodystrophy and lipid abnormalities in the stavudine group."

Finally, in the discussion of HAART-associated clinical events, the link between stavudine and fat maldistribution is specifically downplayed: "Although stavudine has been frequently reported in cases of lipoatrophy, this might be a marker of longer term treatment exposure."

The ATAC/DDC is quite concerned about the aforementioned inconsistencies and the lack of emphasis on toxicity and side effects. These issues are not immediately apparent in the rating system used by the Guidelines Panel. Unfortunately, the system of tables utilized by the panel presents a serious problem. Many do not bother to read anything but the tables. Although safety warnings are in fact included, they are not prominently displayed. On the contrary, they are often buried in long discussions.

We are very concerned that too great an emphasis may have been placed on stavudine's efficacy without ample weight being applied to its resulting toxicities. While we understand that by including stavudine combinations in the A I list you have made provisions for patients who can not tolerate AZT's bone marrow toxicities, we strongly feel that stavudine's preferred first-line usage should at least be qualified with an asterisk which clearly directs readers to prominently displayed warnings about its many toxicities -- including irreversible facial wasting.

We are also requesting that in the future stakeholders have a formal opportunity to comment on proposed Guidelines revisions via a system similar to that utilized by the British HIV Association. We believe that a prescribed method for official comments to proposed updates would prove to be beneficial to community interests and should be instituted as soon as possible.

In closing, the DDC realizes it is a Herculean task to distill guidelines from the voluminous data and the complexities presented by 22 FDA approved anti-HIV treatments. Even though we have expressed concern about the Tables, we agree that the new system is simpler than previous versions and believe it will greatly assist clinicians in prescribing anti-HIV therapy. We thank you and the other members of the Guidelines Panel for your time and effort in this regard. We look forward to your response and to a more formalized mechanism for future comments.

Very truly yours,

Lynda Dee

Co-Chair ATAC/DDC

111 N. Street, Suite 500

Baltimore, MD 21201

LD/jg

d4tguidelines

Vergel

Director, Program for Wellness Restoration (PoWeR)

An all volunteer non profit 501 © 3 organization

www.medibolics.com

www.facialwasting.org

www.atac-usa.org

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