Newsgroup: it.salute.aids
Titolo: R: ABT..primi risultati

 Ciao,
mi chiamo Pierluigi, lavoro come medico infettivologo a Verbania, in
Piemonte, dove stiamo aspettando d'iniziare ad impiegare l'ABT 378 in
expanded-access.
    Vorrei sapere, se non hai nulla in contrario:
1) con quali farmaci assumi l'ABT 378
2) se i trigliceridi erano normali prima di assumerlo
visto che a me risultava che l'unico effetto collaterale fosse la diarrea.
Ciao
Pierluigi

 wrote in message
RBMY5.72471$hk4.2...@news.infostrada.it...


Un link interessante per L' ABT:
http://hiv.medscape.com/Medscape/HIV/journal/2000/v06.n06/mha1208.lube/mha1208.lube.html
Join 18 million Eudora users by signing up for a free Eudora Web-Mail account at 
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 Ciao Giorgio,
sò di essere tonna all'ennesima potenza....ma non riesco ad entrare nel
link: gli dò la password, ma non la prende...in + c'è l'aggravante inglish,
"come faccio ad entrare ???"
Grazie-Tata


Non so che dirti;
Se eri gia' registrata prova ad  andare su 
http://hiv.medscape.com/Home/MyMedscape/MyMedscape.html
dove puoi cambiare la password o rimettertela in mente se ti sei dimenticata;  
Cmq copio-incollo l'articolo cosi' se non riesci ..
 Introduction
With the recent approval of lopinavir/ritonavir (Kaletra) by the Food and Drug Administration (FDA), there is a renewed interest in the clinical use of pharmacokinetics in the day-to-day management of HIV-infected individuals. This dual-protease-inhibitor (PI) combination product containing lopinavir and low-dose ritonavir, previously known as ABT-378/r, has shown encouraging results in both treatment-naive patients[1,2] and those whose first PI-based regimen has failed.[3] In addition, recent data have shown benefit among multi-PI-experienced patients.[4] While these data appear promising, conflicting laboratory methodologies (specifically, different approaches to determining the IC50), selective study inclusion criteria, and noncomparable treatment arms have resulted in confusion among clinicians regarding the optimal role for lopinavir/ritonavir. The purpose of this review is to discuss the role of pharmacokinetic enhancement strategies for HIV-infected individuals with a!
 specific focus on lopinavir/ritonavir. 
 Background
The antiretroviral activity of the PIs has been shown to be directly correlated with drug exposure: The greater the exposure, the greater the viral suppression.[5] Numerous studies have shown that both total drug exposure (eg, AUC)[6,7] and drug levels at selected time points (eg, Cmin)[8-10] correlate with clinical response. Drug exposure can, however, be affected by a number of factors (including interpatient pharmacokinetic variability and protein binding), and antiretroviral efficacy is further influenced by the susceptibility of the specific viral subtype. For example, those patients with high PI plasma concentrations, limited protein binding, and wild-type viral isolates are more likely to obtain good viral suppression than patients with low PI plasma concentrations, high protein binding, and virus with significantly elevated IC50 values. 
With these concepts in mind, it should be apparent that drug resistance is a relative phenomenon and can be overcome if plasma drug concentrations in excess of the virus' increased IC50 values can be achieved. With single-PI-based regimens, it may not be possible to attain sufficiently high drug levels because of excessive pill burden and absorption issues. However, inhibition of cytochrome P450 metabolism, through the use of low-dose ritonavir, can substantially raise the plasma concentrations of most of the commercially available PI agents.[11-13] Thus, pharmacokinetic enhancement strategies using dual-PI-based regimens have been employed in the management of heavily pretreated antiretroviral-experienced patients. If drug exposure could be significantly increased among treatment-naive patients using the same principles, overall clinical response and, potentially, durability of response may also be improved.
 Lopinavir/Ritonavir in Treatment-Naive Patients
Limited data exist on the role of pharmacokinetic enhancement strategies for HIV-infected, treatment-naive patients. The first prospective clinical data were generated by Fletcher and colleagues at the University of Minnesota.[9] Twenty-four antiretroviral-naive patients with viral loads greater than 5000 copies/mL were randomly assigned to open-label concentration-controlled therapy (CC) (n = 11) or standard of care (SOC) (n = 13) with indinavir, zidovudine, and lamivudine. Those patients assigned to the CC arm had their antiretroviral regimens modified as needed to achieve "target" trough concentrations based upon the manufacturer's mean pharmacokinetic trough data (zidovudine = 0.19 mcg/mL, lamivudine = 0.44 mcg/mL, indinavir = 0.15 mcg/mL). Groups were comparable with regards to baseline viral load (4.56 vs 4.42 log10 copies/mL for the CC and SOC arms, respectively). At 6 months, 91% of the CC patients vs 69% of the SOC patients achieved HIV RNA levels less than 50 copie!
s/mL. In addition, patients randomized to the CC arm reached nondetectable viral load levels significantly faster than patients receiving SOC (110 vs 176 days for CC vs SOC, respectively; P = .056). No differences in adverse events were reported between treatment arms. Given that the magnitude of HIV RNA decline predicts durability of response, these data suggest that dosage modifications may improve antiretroviral efficacy and potentially improve the durability of response. Therefore, treatment strategies using dual-PI-based antiretroviral regimens that boost PI levels should provide similar, if not better, clinical results.
Two prospective multicenter clinical trials have evaluated lopinavir/ritonavir for the treatment of HIV-infected, antiretroviral-naive patients. The first trial, M97-720, a phase 2 dose-finding trial, evaluated 100 antiretroviral-naive patients whose median baseline viral load and CD4+ cell count were 4.8 log10 copies/mL and 326 cells/mm3, respectively.[1] They were randomized to 1 of 3 dosing regimens of lopinavir/ritonavir (200 mg/100 mg, 400 mg/100 mg, or 400 mg/200 mg twice daily) in combination with stavudine and lamivudine. At 48 weeks, all patients were switched to open-label therapy at a dose of 400 mg/100 mg twice-daily. By intent-to-treat (ITT) analysis, 78% of patients had HIV RNA less than 50 copies/mL at week 96. In addition, a mean CD4+ count increase of 299 cells/mm3 was observed. There were no differences in clinical responses between the treatment arms. A phase 3 trial, M98-863, randomized 653 antiretroviral-naive subjects to receive either lopinavir/ritonav!
ir (400 mg/100 mg twice daily) or nelfinavir (750 mg 3 times daily) in combination with stavudine and lamivudine.[2] The 2 treatment groups were comparable with regard to baseline viral load measurements (overall mean 4.9 log10 copies/mL) and CD4+ cell counts (overall mean 259 cells/mm3). At week 40, lopinavir/ritonavir outperformed nelfinavir: 79% of patients achieved HIV RNA levels less than 400 copies/mL compared with only 64% of nelfinavir-treated patients (P < .001 by ITT analysis). In both studies, lopinavir/ritonavir was well tolerated and few patients had to discontinue therapy due to adverse events. 
Taken together, these studies suggest that the use of lopinavir/ritonavir for HIV-infected treatment-naive patients results in a potent regimen with durable antiviral response. However, a number of issues must be considered.
First, it should be recognized that these study designs were developed at a time when single-PI-based regimens were the standard of care. We now know that evaluation of single-PI (eg, nelfinavir) vs ritonavir-enhanced PI regimens (eg, lopinavir/ritonavir) may not be an appropriate comparison. In the drug-naive patient, lopinavir/ritonavir will produce plasma levels of lopinavir that are well in excess of the IC50 values for wild-type virus. By comparison, single-PI-based regimens achieve much lower trough plasma concentrations and display wide interpatient variability, with the result that some patients have suboptimal drug levels and are therefore at increased risk for viral breakthrough. This was the theory tested by Fletcher and colleagues[9]; increase plasma trough concentrations from low to high levels and patients will experience increased antiretroviral activity and, potentially, a more durable clinical response. If a single-PI-based comparator arm is to be evaluated !
against lopinavir/ritonavir, one must wonder whether different results would be seen if the single-PI arm was concentration-controlled. In addition, would these results be different if another pharmacokinetically enhanced PI regimen (eg, indinavir/ritonavir or amprenavir/ritonavir) was used in place of or in comparison with lopinavir/ritonavir? How would lopinavir/ritonavir compare with PI-sparing regimens? 
Second, while these data suggest that lopinavir/ritonavir has been well tolerated among treatment-naive patients, it should be recognized that there is relatively limited follow-up with regard to body habitus changes and long-term toxicity effects on cholesterol and triglycerides. In the M97-720 study, 14% of patients had cholesterol levels greater than 300 mg/dL and 11% experienced triglyceride levels greater than 750 mg/dL at the 72-week follow-up evaluation.[14] Will starting therapy with an antiretroviral regimen that achieves such high plasma PI concentrations, along with chronic ritonavir exposure, result in significantly worse effects on lipid profiles and body habitus changes over time? 
Third, little information is available concerning the PI resistance profile that will be seen once these regimens fail. To date, few patients from the trials described above have failed therapy, leaving it unclear how these pharmacokinetically boosted regimens will be salvaged. Given the significantly elevated plasma PI concentrations of these regimens, it is possible that a viral quasispecies with significantly elevated IC50 values will be selected. Will there be significant cross-resistance to the other PIs, and if so, how large will the fold-change in the IC50 values for each agent be? In addition, it should be noted that patient adherence was strictly controlled for in these trials. How will "real world" levels of adherence in the clinic affect the rate of treatment failure and the development of resistance? Only time and experience will allow us to evaluate these critical issues. 
 Lopinavir/Ritonavir in Treatment-Experienced Patients
Lopinavir/ritonavir has been evaluated in patients with both first-PI (study M97-765)[3] and multi-PI treatment failure (study M98-957).[4] In the former, 70 single-PI-experienced, NNRTI-naive patients with viral load measurements between 3.0-5.0 log10 copies/mL were randomized to 1 of 2 doses of lopinavir/ritonavir (400 mg/100 mg or 400 mg/200 mg twice daily) in combination with nevirapine and 2 nucleoside reverse transcriptase inhibitors (NRTIs), at least 1 of which was a new agent.[3] Most patients had prior receipt of indinavir (44%) or nelfinavir (36%), and 63% of patients at baseline displayed at least a 4-fold loss in susceptibility to the previous PI. The median viral load and CD4+ cell count at baseline were 4.0 log10 copies/mL and 349 cells/mm3, respectively. At week 96, 61% of patients in the 400 mg/100 mg arm and 59% of patients in the 400 mg/200 mg arm had HIV RNA levels less than 400 copies/mL by ITT analysis. The mean CD4+ cell count increase from baseline was!
 199 cells/mm3. The most frequent adverse event was diarrhea, reported in approximately 20% of patients. Cholesterol levels greater than 300 mg/dL and triglyceride levels greater than 750 mg/dL were reported in 28% and 25% of patients, respectively. 
The second study, M98-957, evaluated 60 multi-PI-experienced, NNRTI-naive patients who were randomized to receive 1 of 2 doses of lopinavir/ritonavir (400 mg/100 mg or 533 mg/133 mg twice daily) in combination with efavirenz and NRTIs.[4] The higher dose of lopinavir/ritonavir was chosen to compensate for the potential drug-drug interaction between lopinavir and efavirenz. The median number of prior PIs in this cohort was 3,[15] and 68% of subjects had baseline viral isolates that demonstrated at least 4-fold reduced susceptibility to at least 3 licensed PIs. In addition, there was a 9-fold (range, 0.5-96) and 4-fold (range, 0.7-67) decrease in susceptibility to lopinavir in the 400 mg/100 mg and 533 mg/133 mg arms, respectively, at baseline. At 24 weeks, 69% of 400 mg/100 mg treated patients and 82% of 533 mg/133 mg treated patients had HIV RNA levels less than 400 copies/mL by ITT analysis. The mean increase in CD4+ cell count from baseline was 48 and 41 cells/mm3 for the !
400 mg/100 mg and 533 mg/133 mg arms, respectively.
While these data appear extremely promising, especially the M98-957 trial in which multi-PI-experienced were evaluated, several key points should be addressed to place these observed findings in proper context. 
First, in both of these trials patients were NNRTI-naive and received a new NNRTI agent in the regimen. In addition, in the M98-957 trial, approximately 30% of patients also received a new NRTI with which they had not previously been treated, as did all the patients in the M98-765 study. How much did the addition of these agents contribute to the overall clinical outcome?
Second, like all single-PI agents and dual-PI combinations, lopinavir/ritonavir displays wide interpatient variability in plasma drug concentrations. This, coupled with the increase in IC50 values observed in multi-PI-experienced patients, could result in less than optimal antiviral response for some patients. Hsu and colleagues[4,16] from Abbott Laboratories evaluated the impact of individual patients' plasma trough lopinavir concentrations and their individual protein-corrected IC50 values on clinical outcome. When the trough concentrations were 17-fold, 8-fold, and 1-fold above the protein-corrected IC50 value, the predicted clinical response rates were 90%, 80%, and approximately 60%, respectively. This "inhibitory quotient" (IQ) makes rational pharmacologic sense: Patients with high plasma trough concentrations and low IC50 values respond better than patients with low plasma trough concentration and elevated IC50 values. This principle is not unique to lopinavir/ritonav!
ir. These data do suggest, however, that in some multi-PI-experienced patients, the current dosage of lopinavir/ritonavir may be insufficient, especially for those with a low IQ score. Would "shifting" patients with a low IQ score (eg, less than 10) to a high IQ score (eg, greater than 10) through dosage modifications (eg, increase the lopinavir dose to 533 mg/133 mg, 400 mg/200 mg, or greater) improve clinical outcome? Could this be a role for therapeutic drug monitoring?
Third, these clinical data appear not to be unique to the combination of lopinavir/ritonavir. Recent retrospective and prospective data evaluating other PI agents (eg, amprenavir, indinavir, and saquinavir) in combination with low-dose ritonavir have also shown promising results in patients with first, second, and multi-PI failure.[17-23] In addition, data have also shown that patients can be salvaged with ritonavir-enhanced PI regimens employing the PI that the patient previously failed.[19,21,22] Multicenter, prospective clinical trials evaluating both amprenavir/ritonavir and indinavir/ritonavir are currently underway. Unfortunately, until clinical trials comparing lopinavir/ritonavir vs other pharmacokinetically enhanced PI regimens are performed, it will be difficult to determine which regimen works best in which clinical situation. 
Fourth, there are extremely limited data, with short duration of follow-up, evaluating the effects of lopinavir/ritonavir on cholesterol and triglyceride levels, as well as body habitus changes, among heavily pretreated individuals. Unlike clinical trials in which patients are carefully selected, it is likely that many patients in clinical practice who receive lopinavir/ritonavir will have elevated cholesterol and/or triglyceride values at baseline. How will these patients tolerate lopinavir/ritonavir or other ritonavir-boosted PI regimens?
 Conclusions
The recent FDA approval of lopinavir/ritonavir has sparked renewed interest in the concepts of pharmacokinetics and pharmacodynamics in clinical practice. These pharmacokinetic enhancement strategies allow for increased plasma concentrations of PIs with improvements in clinical responses in both drug-naive and antiretroviral-experienced patients. Precisely when agents such as lopinavir/ritonavir are best used has yet to be determined, but this decision will undoubtedly involve a careful assessment of potential risks vs benefits. It is clear, however, that lopinavir/ritonavir has forced all of us to re-evaluate precisely which factors are required for a good clinical response, especially among heavily pretreated antiretroviral-experienced patients. It appears that if sufficient drug is available to inhibit the individual viral isolate, then clinical response will more likely occur. Will it be necessary to use ritonavir-boosted PIs in every situation? Probably not. Will it be !
necessary to use any one particular pharmacokinetically enhanced PI regimen in every situation? Probably not. Each clinical situation will present its own unique set of circumstances, with response being dictated by both the susceptibility of the specific viral isolate and the drug concentration that can be achieved with a given agent. Lopinavir/ritonavir will most likely come to be viewed as only one of many potential choices.
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 Grazie...grazie...grazie...grazie!!!!...Non cel'avrei mai fatta!!!!
Baci-Tata
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