Well, Richard, I guess you are not the only one who thinks Dupont might be interested in Agouron, but personally I hope it doesn't happen.
<<Those costs could drive the independent-and-proud-of-it company into
the arms of a bigger company, some analysts say. Ironically, they think
Agouron would be an ideal acquisition for DuPont, which is expanding its
life-sciences operations. Neither company would comment.>>
And I guess I am not the only "desperate long" who thinks worries are overblown.
That was a very positive article in the WSJ -Heard on the Street
But what would you expect a desperate long to say.
It is too bad earnings are so close to options expiration. I think that is holding the price back.
Earnings will be released after the bell on Tuesday, July 21.
This ones for you, Richard. Some interesting thoughts from the 2nd International workshop on Drug
Kind of an explanation as to why patients who are not undetectable have rising CD4's. This theory says that it is not good to have high number of cd4's especially at beginning, unless the CD4's are CTL's that are anti-HIV specific, and they specifically mention those produced by Remune might offset this.
Those patients with increasing CD4's in spite of detectable viral loads, may not be such a good thing. If they have increased VL because of higher levels of CD4's or who knows which came first, the chicken or the egg?
Theory is that increased CD4's = more target cells, can lead to more mutations.
Unless the CD4s are anti-Hiv specific. Some interesting thoughts from the 2nd International workshop on Drug
Kind of an explanation as to why patients who are not undetectable have rising CD4's. This theory says that it is not good to have high number of cd4's especially at beginning, unless they are anti-HIV CTL's, like Remune,
Those patients with increasing CD4's in spite of detectable viral loads, may not be such a good thing.
Theory is that increased CD4's = more target cells, can lead to more mutations.
Who knows.
Which came first, the chicken or the egg?
>Date: 14 Jul 1998 17:17:43 -0500
>
>TI [ATP DocFax Report] Antiretroviral therapy failure may be related to
>target cell availability - 2nd International Workshop on Drug Resistance &
>Treatment Strategies, 24 - 27 June 1998, Lake Maggiore, Italy
>
>AIDS Treatment Projects "Doctor Fax", issue 49, 10th July 1998.
>AU Paul Blanchard, DocFax Editor.
>
>TX The opening plenary session of the meeting considered the theoretical
>role of target cell (primarily CD4+ lymphocytes) availability in anti-HIV
>treatment failure. Angela McLean of the Institute for Animal Health in the
>U.K. explored the hypothesis that dynamic changes in both CD4+ cell
>populations and viral load under the influence of antiretroviral therapy
>may interact to influence the probability of the emergence of drug
>resistant virus.
>
>Although viral loads fall during treatment, target cells for possible viral
>replication increase. The chance of generating a drug resistant mutant also
>decreases with decreasing viral load. The competition for target cells
>amongst HIV quasi-species (including drug-resistant), however, decreases as
>CD4+ lymphocyte counts rise. The model for generation and extinction of
>strains of HIV with different drug sensitivities developed by Dr McLean
>makes three predictions which could have a major impact on treatment
>strategies.
>
>1. Inadequate virological suppression in the absence of resistance mutations
Treatment may fail to control viral replication and HIV re-emerge even in
the absence of drug resistance mutations. In the maintenance therapy study
ACTG343 patients randomised to stop ZDV/3TC and continue on IDV monotherapy
experienced rebound of virus (n=9) which was wild type. Patient history did
not suggest poor adherence [abs 74]. Similar data were observed in the
SPICE study, with persons with detectable virus at week 16 commonly showing
no typical PI resistance associated mutations [abs 88]. This rebound in the
absence of resistance may not simply relate to insufficient potency of the
therapy but might reflect incomplete prevention of release of infectious
virus from all productively infected cell lines in the presence of an
expanded population of new target cells. Interestingly, both the ACTG343
study mentioned above [abs 74], and a study of viral breakthrough in na‹ve
patients receiving triple or quadruple therapy including 3TC [abs 83],
found that isolates from patients with a rebound in viral load invariably
early
failure to maintain viral suppression may be due to the failure of a single
component of the combination regimen (most often, and most readily 3TC).
This can occur without mutations in the protease region associated with
resistance.
Could it be that compartmentation of both cell types and anatomical
locations are occurring in terms of exposure of HIV to the components of a
combination? If 3TC is the only drug active in certain cell types or
locations, then these reservoirs of HIV are effectively receiving
monotherapy with that compound leading to rapid resistance. M184V mutated
virus would then rapidly seed the increasing numbers of target cells
leading to a rebound in plasma HIV viral load. On analysis, differences
were found in the RT gene [abs 128] and protease gene [abs 112] between
blood and seminal fluid of HIV-infected individuals receiving
antiretrovirals, indicating compartmental variance in resistance. This
supports the hypothesis that the replication and evolution of distinct
populations of virus can occur in an individual. Similar findings have
previously been reported for CSF compared to blood and in untreated as well
as treated patients.
Patients failed on multiple therapies, however, frequently have mutations
consistent with resistance to both RTI's and PI's [abs 85]. It has now been
shown that such multidrug resistant virus is fully capable of being
transmitted. Indeed, a San Francisco based study identified one individual
recently infected with HIV harbouring multiple genetic markers of drug
resistance (RT: D67N, M184V, T215Y, K219Q; PR: M36I, M46I, L63P, A71T,
N88D, V82I, L90M). Unsurprisingly, response to triple therapy (ZDV, 3TC,
IND) was blunted.
>
>Transmission of resistant virus now appears to be a relatively common
>event. In the Swiss cohort of 67 primary infection patients collected in
>Jan 1996-Dec 1997, ZDV resistance was present in 7.5%, and major PI
>mutations (82, 90 +/- other compensatory polymorphisms) in 5%. Resistance
>mutations characteristic of other NAs were infrequent [abs 107]. Similar
>observations were reported in therapy na‹ve patients presenting for care in
>Belgium [abs 113], Iowa [abs 114], Spain [abs 118] and the UK [abs 117].
>Both European groups and US reported individuals seroconverting with HIV
>resistant to PIs, NAs ñ NNRTIs [abs 107, 108] and with the Q151M
>mutinucleoside resistance pattern [abs 123].
>
>2. First few weeks of treatment initiation may be crucial to success
>The first few weeks of antiviral therapy, when both viral load and target
>cell numbers are high, may play a crucial role in the generation of
>partially resistant mutants. If clinically relevant, this observation would
>produce some testable hypotheses. Firstly, rate of viral decay during the
>first few days after treatment initiation could be expected to correlate to
>subsequent likelihood of virological failure. The more rapid the decay (the
>steeper the initial decline, and shorter the time to below detection), the
>less likely or less rapidly would drug resistance be expected to evolve.
>
>Secondly, those who initiate antiretrovirals with lower initial CD4+
>lymphocyte counts may be less likely to generate resistant HIV mutants.
>However, this theoretical advantage may well be offset by a greater number
>of naturally occurring viral quasispecies (due to period and extent of
>prior HIV replication needed to reach lower CD4 counts) and greater
>likelihood of intolerability of medication in more advanced populations.
>Thirdly, artificially lowering CD4+ lymphocyte counts at the initiation of
>antiretroviral therapy (by cytostatics, whole body irradiation or anti-CD4
>monoclonal antibodies for example) may reduce the risk of generation of
>anti-HIV drug resistant mutants.
>
>3. Rapid, large increases in CD4 cell counts in response to combination
>therapy may not be all good
>Large increases in target cell numbers as a consequence of immune
>reconstitution, while reducing risk of opportunistic infections, also
>increases the probability of treatment failure. As Dr McClean explains
>"Since HIV is an obligate parasite, it has no intrinsic growth rate. The
>viral reproduction rate is strongly dependent on the number of target cells
>available in which it can reproduce and therefore increases as a result of
>immune reconstitution." This hypothesis was supported by the observation,
>again in study ACTG343, that virological failure was, indeed, more likely
>in those patients experiencing a large CD4 cell rise [abs 74]. Improvement in HIV specific CTL in concert with rises in CD4+ lymphocyte populations may well offset this effect, but has yet to be reported with PI-containing regimens in chronic infection (although this was reported in hydroxyurea containing regimens - see further article in this issue). Specific induction of anti-HIV CTL responses may be needed to give additional suppression of HIV in the face of increasing target cell availability.
A late breaker presentation at Geneva reported the preliminary efficacy of immune stimulation with a killed gp-120 depleted whole HIV preparation (Remune) as immunotherapy in patients receiving combination therapy [Geneva
abs. 31227]. This study contained a control arm of adjuvant only, and at
week 20 the Remune receiving arm demonstrated strong lymphocyte
proliferative responses to a variety of HIV antigens which were not seen
in
the control arm (more details in the Geneva reports starting in the next
issue of ATP's |
