No, the shorts should worry. A day like today, and it can't break 51?
I know things about AG2034 and AG3340, yes the shorts need to take advantage of this global correction/crash..
P.S. Think double PI:
" Brian Boyle, MD
There is admittedly much we do not know about when and how to use combination therapies of protease inhibitors (PIs) -- alone or in combination with nucleoside or nonnucleoside antiretrovirals -- and much of our current knowledge is based on small pilot studies, according to Dr. John Mellors of the University of Pittsburgh/VA Medical Center. Nevertheless, at the end of the last session on HIV therapy at the worldwide 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Dr. Mellors delivered a cogent review of what is currently known.
<Picture: Back>Standard of Care for 1998 -- RTIs Together With PIs?
Dr. Mellors believes that the standard of care in 1998 will be dual PI therapy with some combination of nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs/NNRTIs). Although dual PI therapy alone is appealing because of the possibility of a well-tolerated BID regimen, legitimate concerns regarding penetration of sanctuary sites, degree of viral suppression, and possible rapid emergence of viral resistance argue against this approach. Especially since many of the drugs in the NRTI and NNRTI classes are now available as 1 pill BID, are generally well tolerated, and achieve excellent levels of viral suppression, PIs in combination with NRTIs/NNRTIs should be, in Dr. Mellors' estimation, the standard of care at this point.
Existing agents -- the list grows. Available agents that could potentially be used in combination drug therapy include saquinavir (both hard and soft-gel); ritonavir; indinavir; nelfinavir; and 141W94, the new Glaxo/Vertex product that is entering phase III trials.
The armamentarium is far from perfect. High doses required to achieve and maintain adequate drug levels, large numbers of pills and frequency of dosing, and extensive side-effect profiles make compliance difficult, even for the most motivated patients. High variability in absorption, metabolism, and protein binding make dosing difficult for the physician. Drug trough levels may sometimes fall very close to the IC50 of the drug, which may provide a "window of opportunity" for mutations that lead to viral resistance.
Accentuate the positive. Dr. Mellors discussed the positive and negative aspects of dual therapy. In his opinion, the benefits outweigh the drawbacks. The benefits of dual therapy are:
Improved pharmacokinetics, which allows for higher areas under the curve (AUC), less drug-level variability, fewer pills, and twice-daily dosing;
Increased viral inhibition with possible synergistic effects;
Delayed resistance resulting from improved drug delivery and compliance; and
Fewer toxicities and side effects due to decreased dosing requirements.
These benefits are countered by concerns regarding:
Possible drug interference or antagonism at the active site of the protease;
The possibility of CNS escape of viral replication due to poor CNS penetration;
The possibility of new or more frequent side effects, making compliance even more difficult; and
The possibility of inducing complete protease inhibitor resistance.
Eliminate the negative. Based on current data, it does not appear that antagonism at the active site of the protease occurs. Decreased drug penetration into the CNS is balanced by the low level of protein in the CNS compared with that in serum; thus free drug levels approach those of serum. These rebuttals are far from definitively established. Furthermore, other issues, such as penetration into "sanctuary sites" and lymph node tissue, must be addressed before these concerns are dismissed.
The role of PIs. The goals of PI therapy are to "increase the punch" using fewer pills and less frequent dosing and to delay, for as long as possible, the emergence of resistant strains of virus. A further consideration, not discussed by Mellors, is to decrease costs and increase the overall cost-effectiveness. Cost remains a major obstacle to many patients.
<Picture: Back>Potential Combinations
Dr. Mellors reviewed existing data on combinations of protease inhibitors. For any given combination, data on (1) pharmacokinetics, (2) AUC and trough drug levels, (3) the frequency of dosing and pill counts, (4) antiretroviral activity, (5) the likelihood of the emergence of resistance, and (6) the frequency of side effects should be gathered (Table 1). In many cases, these data are yet to be collected.
400/400... Ritonavir and saquinavir (either soft or hard gel) is a relatively well- studied combination. It is well known that 400mg of ritonavir plus 400mg saquinavir (hard gel) BID achieves viral suppression, decreases pill count and dosing frequency, and increases tolerance to therapy. The ritonavir 400/400 BID regimen has been shown to be better tolerated than regimens using higher doses of saquinavir, while maintaining efficacy in decreasing viral load.
...Or 400/600. However, emerging data indicate that the viral suppression may not be complete. Talal and colleagues of the Rockefeller University studied patients treated with a 4-drug regimen of ritonavir, saquinavir, zidovudine, and lamivudine who achieved undetectable serum viral loads. Tonsilar biopsy specimens from 2 of 6 of these patients contained MS mRNA, and US mRNA was detected in colon biopsies from 4 of 6 patients. Failure of this regimen, the authors found, was usually due to the emergence of ritonavir resistance.
These data strongly suggest that patients should be advance to a higher dose of ritonavir -- 600mg BID -- if they are able to tolerate it. At the higher dose, ritonavir contributes a direct antiviral effect, which may help avoid development of resistance. Only patients who cannot tolerate the increase should be allowed to remain on lower doses.
Ritonavir and saquinavir soft gel. Data are accumulating that ritonavir and saquinavir (soft gel) are also effective and, like the hard-gel combination, the combination reduces pill counts, frequency of dosing, and side effects.
Ritonavir and indinavir. Preliminary results from ongoing studies of a ritonavir and indinavir combination suggest that ritonavir decreased indinavir clearance and smoothed its large peak/trough swings. In 1 study, presented at this conference by Hsu and colleagues, indinavir 400mg BID plus ritonavir 400mg BID achieved indinavir levels comparable to an 800-mg TID dosing schedule, with no effect on ritonavir levels. This combination may eventually allow for BID dosing. However, the antiretroviral activity and resistance issues of this combination are unknown, and should be investigated before the approach is implemented.
Combinations galore. In addition to above, there are preliminary studies involving ritonavir and nelfinavir; indinavir and nelfinavir; nelfinavir and indinavir; and 141W94 in combination with saquinavir (soft gel), indinavir, nelfinavir, and zidovudine/lamivudine (Table 1)." |
