As far as Canadian approval, it should have more of an impact than Japanese approval, where Agouron only gets royalties from Roche on sales of Viracept.
Agouron will have to pay 19%-20% of Viracept sales to Japan Tobacco, the remainder of revenues goes to Agouron. And marketing and expanded access trial expenses should go down now.
Also, Canada's national health program automatically pays for all treatment, although I think that drugs are under a special program, which is subsidized by the government.
There is a network of HIV experienced physicians in Canada, CHAPS, that provides the latest up-to-date care. Montaner, one of the big presenters at Geneva, is from BC.
A 1996 article from AEGIS said there were over 44,000 HIV positive individuals in Canada, in contrast to an estimated 10,000 in Japan.
Abbot is not able to predict when they will be able to start production of Ritonavir in a new facility. apparently it could be awhile, like at least 6 months, maybe more. I can't imagine too many new prescriptions will be written for ritonavir until it is known when it will be available. Apparently the liquid form, which will be available, has a terrible taste, and will make adherence more difficult, especially in children.
I never considered nonnucleoside reverse transcriptase inhibitors as anything more than a complement to protease inhibitors, i.e. to be used together, as the literature is full of articles about the quick resistance that develops on NNRTI's, their side effects like rash, elevated liver enzymes, pancreatitis, nausea, mental confusion, headaches, diarrhea, etc etc
A very important point is durability. Is the response to NNRTI's sustained?
Apparently not. The response to a drug combination including NNRTI's and NRTI's peaks at 16 weeks. It is no coincidence that Dupont changes the drug regimen at 16 weeks if patients are not responding (study 005, 006). They say they changed patients' regimens at 16 weeks, but they never say how many were changed. In the Sustiva studies as well as Nevirapine, responses peaked at 16 weeks and then declined, when protease inhibitors were not used.
Don't forget that those 'eye-popping' results that Joseph Eron referred to only included data from 11 patients at 36 weeks, in Dupont 006. Thirty seven patients started in that treatment arm. So the 95% undetectable is actually more like 30%. And that was in treatment na‹ve patients. The responses to a NNRTI plus nuke regimen in treatment experienced patients is much weaker, if present.
A pharmacist posted the following explanation on the Crix List as to why the response on NNRTI's is limited in durability:
>>Reverse transcriptase inhibitors act inside the cell; protease inhibitors act
inside the virus and probably inside the cell as well. The other key point
is the "active" (or "stimulated") vs "resting" (or "quiescent") cell dilemma.
In vitro studies have demonstrated enhanced activity of d4T and ZDV in
"active" cells and enhanced activity of ddI, 3TC, and ddC in "resting"
cells (1).
Keep in mind that the drugs are effective in both types of cells but there is
preferential activity in one cell-type over the other. NNRTIs and PIs
are probably equally active in "active" and "resting" cells.>>
<<99% of HIV replication occurs in "active" cells and the substantial reduction
in viral load with initial therapy probably reflects the destruction of
virus in these cells. Then there is the pool of cells that are infected but aren't
active (i.e.they are resting). These cells may harbor virus for a very long time making
eradication of HIV difficult.>>
<<Reverse transcriptase inhibitors (NRTIs and
NNRTIs) only works on viral RNA before it is integrated (the "acutely"
infected cell). The cell that already has HIV integrated does not rely on
reverse transcriptase and can go on to shed virus ("chronically" infected).
PIs and probably hydroxyurea are the only drugs currently available that
work on these cells.>>
<<And this is where you would pharmacologically be losing coverage for
"chronically" infected cells because you do not have a PI. In the short-run,
viral replication will be reduced in the "acutely" infected pool of cells
but in the long-run, durability is unlikely and a person is likely to fail.>>
(1) Gao et al. Divergent anti-human immunodeficiency virus activity and
anabolic phosphorylation of 2',3'-dideoxynucleoside analogs in resting and
activated human cells. J Biol Chem 1994; 269: 12633-12638
The following was posted to the Crix list, about a week ago:
>I've been hoping that I could substitute Sustiva for Viracept, given that the
>hype is that it's as good a viral suppressor as Crixivan in combination
>therapy. I figured I could avoid the PI's lipid problems if I used a
>different class of drug.>
>However, when I talked about this idea with my Doctor today he said Sustiva's
>strength is over estimated. According to him, it is very potent initially, but
>easy to mutate around (needing only a couple of codon site mutations vs. more
>for PIs) and the viral rebounds are sudden and extreme when break-throughs
>occur. He says he got his info from one of the researchers developing this
>drug that he recently talked to.>
>He also said he's heard of lipid problems with Sustiva as well! Very
>discouraging.>
>All in all, he didn't recommend switching.
______________________
Resistance to NNRTIs develops quickly, and causes cross resistance to the other NNRTI's, eliminating one class of drugs as an option for future treatment, not the point of a 'protease-sparing' regimen.
"In this regard delavirdine is similar to the other non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTI), all of which select rapidly for point mutations that confer high-level drug resistance. Thus, delavirdine can be considered one of the so-called "fragile" drugs that should only be used in combination with other potent agents in order to limit emergence of drug resistance. Early studies tested the activity of delavirdine in combination with ZDV or ddI in patients failing nucleoside therapy. Not surprisingly, these studies showed only a transient benefit of DLV. Nevirapine (NVP) suffered a similar fate until the INCAS study, which was conducted in treatment-naive patients, demonstrated the potency of the triple-drug combination of ZDV+ddI+NVP. The current study by Para et al overcomes many of these earlier limitations by combining DLV with 3TC and focussing on a patient population with limited prior treatment experience.
healthcg.com
There are also many more side effects than publicly acknowledged. The 600 mg dose of Sustiva that Dupont plans on using produced the most side effects, had the highest dropout rate compared to 200 or 400 mg doses and showed the lowest increase in CD4+.
From a JAMA article on nevirapine:
"The most frequent laboratory test abnormalities were elevated gamma-glutamyltransferase (17% [26/151]),
alanine aminotransferase (14% [21/151]),
creatine phosphokinase (12% [18/151]),
aspartate aminotransferase (11% [17/151]),
amylase (7% [11/151]), total bilirubin (4% [6/151]),
and hemoglobin (1% [2/151]) levels and decreased neutrophil count (5% [7/151]).
Overall, 26 (27%) of 98 patients treated with nevirapine developed at least 1 laboratory test abnormality, compared with 6 (11%) of the 53 patients treated with zidovudine plus didanosine (P=.04).
Elevated liver function test results were seen in 14 (30%) of 47 patients in the nevirapine plus zidovudine group, in 12 (24%) of 51 patients in the nevirapine plus zidovudine plus didanosine group, and in 6 (11%) of 53 patients in the zidovudine plus didanosine group.
Five patients treated with nevirapine stopped taking the study medication permanently because of elevated alanine aminotransferase levels. In all 5 cases, alanine aminotransferaselevels normalized after the patients stopped taking nevirapine. Other laboratory abnormalities occurred with comparable frequency in each treatment group."
A table listing Adverse Effects seen in a study in patients on Nevirapine, AZT, 3TC.
ama-assn.org
________________________________________________________
Barely mentioned are serious birth defects found to occur in pregnant monkeys receiving Sustiva (efavirenz). natap.org
"The Division of AIDS of the NIH issued a safety alert regarding efavirenz based on the data reported. The following language has been added to all study protocols using efavirenz: "Studies using DMP-266 (efavirenz) in pregnant monkeys have shown newborn monkeys with abnormalities at birth. Three out of 13 monkeys were born with birth defects. One monkey had a defect in the roof of the mouth (cleft palate), another monkey had small eyes (microphthalmia), and another was born without a brain (anencephaly) and missing one eye (anophthalmia). The monkeys in this study received doses of DMP-266 similar to those that are being studied in humans." DMP-266 was administered during the first trimester of pregnancy for these animals, when fetuses are at the greatest risk. It is not known whether this could happen in humans fetuses; therefore, you should not become pregnant while taking DMP-266." The safety alert is based upon preliminary findings. The relevance to humans is not known and follow-up information will be provided, as it becomes available. "
And then of course is the "minor side effect"of Glaxo's Abacavir (1592). The hypersensitivity reaction, present in 3% to 5% of patients, can be fatal, if patients are "re-challenged."
Seems to me that unproven drugs like Sustiva and Abacavir are being hyped, without adequate data to support safety, efficacy, or durability. There is no data yet to support patients switching from protease inhibitors to NNRTI's and then back to PI's if it doesn't work.
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