LONG TERM DATA SUPPORTS TWICE DAILY ADMINISTRATION

Studies continue to expand the VIRACEPT^® (nelfinavir mesylate) knowledge base, supporting its role as an optimal first PI to preserve other treatment options, as well as its use in convenient twice-daily (or BID) dosing regimens. These new data were among those presented at the 39^th Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco.

VIRACEPT As The "First" Protease Inhibitor

A new study presented by Dr. Haubrich¹ has found that patients treated with VIRACEPT before using other protease inhibitors (PIs) are less likely to develop cross-resistance to other PIs even if HIV resistance to VIRACEPT develops. The multicenter California Collaborative Treatment Group study examined differences in protease inhibitor phenotypic susceptibility after failure of a patient's first PI-containing regimen.

The trial studied 116 patients with a median HIV RNA of 4.1 log₁₀ copies/ml and a median CD4 cell count of 295 cells/mm³; 96 patients had received prior PI therapy. In patients previously treated with VIRACEPT, viral isolates remained susceptible to FORTOVASE^® (saquinavir) and amprenavir in the majority of cases. Only 29% of patients who had received VIRACEPT had reduced susceptibility to 2 or more PIs; 70% of patients with prior indinavir experience had reduced susceptibility and 43% with other prior PIs had reduced susceptibility (p=0.001).

Conversely, 84% of patients had viral isolates that remained susceptible to FORTOVASE, and 83% responded to amprenavir.

The varying degrees of cross-resistance reported suggest that prior use of indinavir is associated with greater cross-resistance than prior use of the other PIs studied. These data lead the researchers to suggest that when VIRACEPT is used as the first PI, it is associated with less cross-resistance than the other available PIs, thereby preserving patient treatment options.

VIRACEPT Twice-A-Day: the Women First Study

Data presented by Dr. Clark² from a 48-week prospective study, known as the Women First Study, evaluated two combination regimens in women naïve to PIs, d4T and 3TC: VIRACEPT 1250-mg BID (or two times a day) + FORTOVASE 1000-mg BID + standard

doses of d4T and 3TC or VIRACEPT 750-mg TID (or three times a day) + FORTOVASE 600-mg TID + standard doses of d4T and 3TC.

An intent-to-treat analysis of the data found that the BID arm was more effective than the TID arm in reducing viral load (HIV RNA <50 copies/ml = 67% vs. 50%, respectively) and demonstrated similar increases in CD4 cell counts (182 cells/mm³ and 170 cells/mm³, respectively). The study also assessed the effect of these two regimens on several markers of metabolic function: cholesterol, triglycerides, and glucose. There were no significant differences between the two arms, but both arms caused small elevations of these markers.

VIRACEPT Helps Patient Adhere Better to Treatment, Study Shows

Data from a prospective study examining drug efficacy and patient convenience -- believed to be a strong factor in patient adherence -- were presented by Dr. Roca³. One hundred twelve treatment-experienced patients were randomized to one of two arms: VIRACEPT + d4T + 3TC or indinavir + d4T + 3TC. Most significant was the difference between the groups in their actual drug adherence levels. At 6 months, 70% of subjects taking VIRACEPT were adequately adherent, while only 48% of the indinavir group demonstrated adequate adherence (p = 0.0311). Side effects also proved to be a factor in adherence, with 12% of those on VIRACEPT discontinuing their participation by
6 months while 34% of patients on indinavir discontinued their drug regimen due to side effects during the same period.

The researchers conclude that while the efficacy of both regimens was similar, those on the VIRACEPT-containing regimen displayed a stronger level of adherence, which may translate into longer lasting virological benefit when compared to those receiving indinavir.

Protease Inhibitors Suppress Viral Load Longer Vs. Protease-Sparing Regimen

Julio Montaner, M.D., St. Paul's Hospital, Vancouver, presented retrospective data from a study comparing the durability of three drug regimens, two of which used protease inhibitors and one of which was protease-sparing⁴.

Data on 151 patients on triple therapy from the INCAS (AZT + ddI + NVP), AVANTI 2 (indinavir + AZT + 3TC), and AVANTI 3 (VIRACEPT + AZT + 3TC) trials with an HIV-RNA nadir between 20 and 400 copies were combined into a single database. After controlling for baseline differences in viral load, CD4 count, and adherence among the three trials, there were statistically significant differences in the times viral load remained below 500 copies/ml, below 1,000 copies/ml, and 1 log₁₀ below baseline levels.

Among the patients who were between the limit of quantification and 400 copies/ml, those assigned to either protease inhibitor-containing regimen had longer virologic suppression than those assigned to AZT + ddI + NVP, the NNRTI-containing regimen.

VIRACEPT + Delavirdine Boosts VIRACEPT Blood Concentrations

Another prospective, 48-week study (the first of two parts) presented by Dr. Slater⁵ examined the ability of delavirdine (DLV), an NNRTI, to increase blood concentrations of VIRACEPT. Twenty-two HIV-infected individuals were randomized in the study to receive either delavirdine 400-mg TID or 600-mg TID in conjunction with VIRACEPT 750-mg BID + d4T 40-mg BID + ddI 200-mg BID for 48 weeks. Mean baseline values were viral load of 4.85 log₁₀ copies/ml and CD4 count of 372 cells/mm³. Mean VIRACEPT trough concentrations with DLV were roughly twice those seen from historical data with a VIRACEPT 750-mg TID regimen without DLV.

Mean reduction of viral load was greater in the DLV 600-mg arm at both weeks 24 and 48. Of the 13 patients who were available to be evaluated at week 48, 69% had viral loads below 50 copies/ml for the entire 48-week period. The researchers suggest that the durability and efficacy demonstrated in this trial support the potential use of DLV 600-mg with VIRACEPT in a BID regimen.

Dr. Gatell⁶ presented results from part two of this prospective study of the effect of delavirdine in increasing VIRACEPT concentrations in the blood. The study tested the safety, efficacy, and tolerability of DLV BID in one of four treatment arms:

• VIRACEPT 1250 mg BID + d4T 40 mg BID + ddI 200 mg BID;
• VIRACEPT 1250 mg BID + DLV 600 mg BID + d4T 40 mg BID + ddI 200 mg BID;
• VIRACEPT 1250 mg BID + DLV 600 mg BID + d4T 40 mg BID; or
• VIRACEPT 1250 mg BID + DLV 600 mg BID + ddI 200 mg BID.

While more than 175 HIV-infected, NNRTI- and PI-naïve, minimally ddI-experienced
(< 1 month) individuals have enrolled in the trial, week 24 data are currently available on only 45 patients. Baseline laboratories for all enrolled patients showed a mean viral load of 4.9 log₁₀ copies/ml and a mean CD4 count of 306 cells/mm³ at week 24.

All four arms reported a mean reduction of 2.6-2.7 log₁₀ in viral load with 81% achieving <400 copies/ml and 67% achieving <50 copies/ml. There was also a mean increase in CD4 count of 183 cells/mm³. The researchers suggest that these data show the efficacy and potential durability of a BID regimen combining DLV and VIRACEPT plus d4T and/or ddI.

Saquinavir + Ritonavir: Effective Following VIRACEPT Therapy

Dr. Zolopa⁷ presented the results of this retrospective multi-center study that systematically screened medical records, pharmacy records, and electronic databases to identify patients who had taken VIRACEPT as their first PI, had a documented 1 log₁₀ decline in HIV viral load; had a rebound of more than 0.6 log₁₀, and were placed on a salvage regimen of RTV + SQV with or without NAs. Data available on 79 patients show baseline (the point of the change to SQV + RTV) values of a median CD4 of 219 cells/mm³ and a viral load of 4.52 log₁₀.

The researchers suggest that these data support previous pilot clinical trials that demonstrate the potential for using SQV/RTV after VIRACEPT with substantial and durable antiretroviral activity.

…With Calcium Supplements

Dr. Perez-Rodriguez⁸ presented data from this open-label, prospective study that enrolled 15 patients with a history of diarrhea induced by VIRACEPT and treated with at least one prior anti-diarrheal medication with unsatisfactory results. At baseline, all but three patients had viral loads below 400 copies/ml and a mean CD4 cell count of 565 cells/mm³. Patients were given a short battery of questions to assess their symptoms and then given 500-mg calcium tablets BID to take with their VIRACEPT. After 48 hours of treatment, they were asked an additional series of questions to determine any changes in their bowel movements. Prior to calcium treatment, 40% classified their symptoms as mild, 47% as moderate, and 13% as severe.

After a minimum of 48 hours of calcium supplementation, 87% reported normal stools and the remaining 13% reported only mild diarrhea symptoms. No side effects were associated with calcium use. The researchers suggest that calcium supplementation might be an effective, low-cost intervention to address this type of diarrhea.

…With Psyllium

In similar study, Dr. Ronagh⁹ presented data from a short prospective study that enrolled 16 patients with symptoms of PI-associated diarrhea refractory to treatment with anti-diarrhea medications to assess the effect of psyllium husk fiber bars on their symptoms. Fourteen patients completed the study. At baseline, mean HIV viral load was 4.84 log₁₀ copies/ml and mean CD4 count was 275 cells/mm³. Questionnaires were used before and after the study to assess the state of the patients' symptoms and the taste of the bars. Patients were provided with dietary counseling and two weeks' worth of psyllium husk fiber bars. Prior to treatment, 29% classified their symptoms as mild (grade 1), 64% as moderate (grade 2), and 7% as severe (grade 3), with a mean overall grade of 1.78.

After two weeks of using the bars, 93% of patients reported that their symptoms improved: 50% reported normal stools, 29% reported grade 1, and 21% grade 2, for a mean overall grade of 0.93. All of the patients reported liking the taste of the bars and 86% continued to use the bars after the end of the study. The researchers suggest that psyllium husk fiber bars might be an effective, low-cost intervention to address one of the main side effects of PI-induced diarrhea.

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