Re: Stopping Zerit

[Guest guest]

It’s not a drastic action at all if you have something else to replace it with, such as Viread. I don’t know what else you’re taking but you may be able to get Coviracil very soon. That might work too. The important thing is to write a letter to the FDA or call them and explain the situation. Call BMS and tell them you are stopping for this reason and you’re mad. Tell your doctor to report the facial atrophy to the FDA. That is the way that a warning label gets put on a drug, especially in the case of something that the FDA is inclined to consider a cosmetic issue. Explain to them that having to have facila reconstruction surgery is NOT a cosmetic side effect of a drug. If anyone says you’re lucky to be alive, tell them tens of BILLIONS of dollars have already been made on HIV drugs and you want better service from the manufacturer. Tell the FDA that you think Serostim should be approved for HARS as well, with preserved bacteriostatic water and smaller doses. We’re already on your side. Tell them!

[Guest guest]

At 08:21 PM 6/7/2003 -0700, you wrote:

>Dear Friends:

>I have made the decision to stop taking Zerit/D4T. I have been on it for

>7 years and it was the only drug that has actually worked for me this

>entire time. However, I believe in quality of life, not quantity. After

>spending $3,500.00 on Newfill only to see it slowly slip away, I am not

>anxious to return to my former skeletal face. If stopping the Zerit will

>help save my face but shorten my life so be it. Only when people like me

>resort to drastic actions like this will the drug companies, FDA and

>others take notice. They must be made to realize that lipoatrophy and

>lipodystrophy are serious and real issues facing the HIV community and

>that some of us would rather be dead than look like we were.

This is precisely why we need the kind of studies, as Ken points out, the

pharmaceutical companies simply won't do. Perhaps 40 mg per day instead of

80 would have prevented the destruction and the consequent urge to drop

Zerit. I trust, though, that you will be able to switch to another

successful regimen!! Is it possible (i.e., CD4 are above 300-350) that you

could take a structured treatment interruption?

When they started with AZT, it was 1200 mg. Then 600 mg. Is it too rash to

say 300 mg--especially in the context of ARV--works just as well? Perhaps.

Of course, what I originally said was that there are data SUGGESTING it

may. Not that it does. But JB decided to get his knickers in a twist. We'll

never know because cutting the dose in half means half the profits unless

they double the number of recipients. For him to say there are NO data is

inaccurate. There are some (see below). But they are inadequate.

So people are left with minimal information on which to base treatment

choices. However, you will note that the one AZT-ddI study below suggests

that even 150 mg AZT with ddI was about the same in efficacy as 600 mg

AZT/500 mg ddI. Once again, JB, you have made the declarative statement

that there are no data without actually researching the issue very far.

This frustrates me.

There are issues with subtherapeutic dosing that may lead to resistance, it

is true--but this seems to be a problem to which protease inhibitors and

NNRTIs are more exquisitely sensitive. Indeed, there are data suggesting

that myristoylation of nukes may enhance their bioavailability, according

to a recent and fascinating article in Lipids. A number of preliminary

studies were done but no clinical research.

Finally, even Ann Collier in her email to you which you were kind enough to

share with me and the group indicated a more nuanced analysis. There were

situations in which the data, tho limited due to the numbers enrolled,

where an indication of 300 mg were supported by the extant data. I repeat

that information.

JB, you really dislike me. I know that. You inspire a fair amount of anger

in me, too. Playing this civilized nonsense and pretending you don't have

the most profound rancor is a kind of game that doesn't lead to any kind of

resolution. You most certainly would like to pick a fight. And I think it

is important to acknowledge that and those feelings. And sadly, this

influences the way we treat each other and the way we respond to problems.

I don't have any quick answers for this. I suppose it's something we will

have to live with and I hope we can do so in a way that does not create

animosity or strife in the group that turns people off. One thing I'm

certain of: neither you nor I needs this kind of tension in our life. I

don't want to cause you suffering.

There IS a good side to this. If you weren't so damned obnoxious sometimes,

I probably wouldn't have gone to the extra trouble to look into these data

and try to justify my comments. LOL....so I HOPE that after all, our small

feuds wind up being helpful for others and ultimately even good for you and

me, in ways both tangible and intangible.

M.

****

Tartaglione TA, Collier AC, Opheim K, Gianola FG, Benedetti J, Corey

L. Pharmacokinetic evaluations of low- and high-dose zidovudine plus

high-dose acyclovir in patients with symptomatic human immunodeficiency

virus infection. Antimicrob Agents Chemother. 1991 Nov;35(11):2225-31.

Department of Pharmacy Practice, School of Pharmacy, University of

Washington, Seattle 98105.

The pharmacokinetics of zidovudine were evaluated in 41 patients with

Centers for Disease Control HIV class IVA infection. The patients were

assigned escalating doses of zidovudine (300, 600, or 1,500 mg daily) and

were randomized to receive either zidovudine alone or zidovudine with a

high dose of acyclovir (4,800 mg per day). Single and multiple intravenous-

and oral-dose pharmacokinetic studies were performed on days 1 and 7 and

weeks 6 and 12 of therapy. Zidovudine concentrations were analyzed by

high-pressure liquid chromatography. Pharmacokinetic parameters were

estimated by noncompartmental methods. Zidovudine concentrations in serum

declined in a biphasic manner, with half-lives ranging from 1 to 2 h, and

were independent of acyclovir administration or length of zidovudine

therapy. The median time of peak concentrations in serum following oral

doses was 0.75 h (range, 0.25 to 3 h). Accumulation of zidovudine in serum

was not observed, but the maximum concentration of drug in serum (Cmax) and

the area under the concentration-time curve increased proportionally with

increased zidovudine doses. Mean day 7 oral Cmax values were 0.20 +/- 0.12,

0.55 +/- 0.33, and 1.0 +/- 0.5 micrograms/ml for 17 patients receiving

total daily doses of, respectively, 300, 600, and 1,500 mg of zidovudine

alone, whereas Cmax values were, respectively, 0.27 +/- 0.18, 0.43 +/-

0.33, and 1.2 +/- 0.80 micrograms/ml for 15 comparably treated recipients

of zidovudine plus acyclovir (P was not significant). The median

bioavailability of oral zidovudine was 67% (42 to 120%) and did not vary

with dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

****

Collier AC, Coombs RW, Fischl MA, Skolnik PR, Northfelt D, Boutin P, Hooper

CJ, Kaplan LD, Volberding PA, LG, et al. Combination therapy with

zidovudine and didanosine compared with zidovudine alone in HIV-1

infection. Ann Intern Med. 1993 Oct 15;119(8):786-93.

University of Washington School of Medicine, Seattle.

OBJECTIVE: To assess safety, pharmacokinetics, and in-vivo virologic

activity of five different combination regimens of zidovudine and

didanosine compared with zidovudine alone in patients with human

immunodeficiency virus type 1 (HIV-1) infection. DESIGN: Open-label,

partially randomized, dose-ranging study. SETTING: University-affiliated,

medical center clinics. PATIENTS: A total of 69 patients with HIV-1

infection, CD4+ cell counts fewer than 400 cells/mm3, and fewer than 121

days of previous zidovudine treatment. INTERVENTIONS: Fifty-five patients

received combination therapy with zidovudine and didanosine, and 14

received zidovudine therapy alone (600 mg/d). Daily dosages in milligrams

of zidovudine and didanosine, respectively, in the five combination groups

were 150 and 90 mg, 300 and 334 mg, 600 and 334 mg, 300 and 500 mg, and 600

and 500 mg. MEASUREMENTS: CD4+ cell counts, HIV-1 RNA titers in plasma, and

toxic effects. RESULTS: The combination regimens were associated with

higher and more sustained increases in CD4+ cells than zidovudine alone,

even after adjustment for initial CD4+ counts and previous zidovudine

therapy (P < 0.001). The median increase in CD4+ cell counts was 166

cells/mm3 with combination therapy and 77 cells/mm3 with zidovudine alone

(P = 0.001) and did not differ statistically among the five combination

regimens. Human immunodeficiency virus type 1 RNA titers in plasma

decreased in 15 (83%) of 18 combination-therapy recipients compared with 2

of 7 zidovudine-alone recipients (P = 0.017). No pharmacokinetic

interactions were seen between zidovudine and didanosine. Toxicity rates

were low among all treatment groups. A greater decrease in hemoglobin

levels was seen with the regimen using zidovudine alone (-8 g/L) compared

with combination regimens using the same zidovudine dose (-1.5 g/L, P =

0.03). CONCLUSIONS: Combination therapy with zidovudine and didanosine

produced larger and more sustained increases in CD4+ cell counts, more

frequent decreases in plasma HIV-1 RNA titers, and more stable hematologic

status than zidovudine therapy alone. The effects of this combination on

the progression of HIV disease merit further study, to provide information

about clinical outcome, because this was a relatively small study based on

surrogate markers of HIV-1 infection.

***

I was involved with a few of these studies - zidovudine 600 mg/day was as

good as 1200 mg/day for HIV disease progression. A much smaller study

showed that 300 mg/day showed similar results as 600 mg/day and 1500

mg/day. (However, this latter study was too small to say they were

equivalent.) I am not aware of any studies addressing these issues with

HAART regimens. The issue of ZDV dosing was overshadowed in importance when

HAART came on the horizon and more nucleoside choices became available. I

think the data support use of ZDV 300 mg (was used 100 mg TID) if there is

toxicity with a higher dose and other nucleosides aren't an option.

*******************************************************************************

Ann C. Collier, MD

206/731-3293 Professor of Medicine

206/731-3483 (fax)

University of Washington School of Medicine Director, AIDS Clinical Trials

Unit Harborview Medical Center, Box 359929

325 9th Avenue

Seattle WA 98104

acollier@...