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The two studies were presented during the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Further research is already underway in a larger study in at least 400 patients of twice-daily Crixivan 1200 mg in combination with AZT and 3TC, compared to the current three-times-a-day regimen of Crixivan (800 mg every 8 hours) in triple therapy. Twice-daily dosing for Crixivan is being studied by Merck because it may make it easier for patients to adhere to their antiviral medication schedule. Other combination studies using twice-daily Crixivan with other medications such as nelfinavir, efavirenz (DMP-266) and GW1592 are also ongoing.

Twice-Daily Dosing Trial with Crixivan Provided Encouraging Preliminary

Results

Preliminary results from the first controlled pilot study of Crixivan 1200 mg taken twice-daily in triple therapy showed 75% of patients (12/16) had HIV suppressed below the limit of detection (less than 500 copies/mL) after 20 weeks of therapy with a combination of Crixivan 1200 mg twice daily and AZT/3TC (300 mg/150 mg twice daily). The clinical significance of reductions in viral load are not known.

"These results are encouraging in determining the effect of a twice-daily dosing regimen with Crixivan," according to Dr. Bach-Yen Nguyen of Merck Research Laboratories who presented the data. "However, these results are preliminary and need further validation. That's why Merck has initiated a larger trial to provide further evidence that the twice-daily regimen will suppress HIV below detection as well as the current dosing regimen for Crixivan."

In patients taking twice-daily Crixivan at 1200 mg every 12 hours, the median viral load reduction was 2.20 log10(f) copies/mL, and the median increase in CD4 cell counts was 61 cells/mm3(g). Among patients in the study's control arm who were taking Crixivan three times a day in triple therapy with AZT and 3TC, about 54% of patients (7/13) had HIV suppressed below the limit of detection (less than 500 copies/mL), the median viral load reduction was 1.43 log10(f) copies/mL, and the median increase in CD4 cell counts was 85 cells/mm3(g) after 20 weeks of therapy. Similar adverse events were reported for the two study arms. This ongoing, 52-week pilot study of Crixivan taken twice-daily includes 87 patients who had between 150 and 500 CD4 cells/mm3(g); 90% had taken AZT, and no patients had previously taken 3TC or a protease inhibitor.

Most Patients' HIV Undetectable for Two Years in Study 035

Roy Gulick, M.D., of the New York University School of Medicine/Bellevue Hospital, presented 100-week results from Merck's landmark Study 035. Seventy-nine (79) percent of patients (22 of 28, all AZT-experienced) taking triple therapy with Crixivan, AZT and 3TC sustained "undetectable" levels of virus (less than 500 copies/mL) for almost two years. The median decrease in viral load from baseline was 2.12 log10(f) copies/mL, and the median increase in CD4 cell count was 230 cells/mm3(g).

Crixivan is indicated for the treatment of HIV infection in adults when antiretroviral therapy is warranted. This indication is currently based on analyses of surrogate endpoints (viral load reductions and CD4 cell count increases) in studies of up to 24 weeks in duration.

Study 035 was one of the first studies to evaluate a protease inhibitor in triple therapy in patients previously treated with antiretrovirals such as AZT. Patients (97 total) in this study had taken AZT for a median of 2.4 years, but had not taken 3TC or a protease inhibitor; 81 percent already had virus that was resistant to AZT. Baseline median CD4 count was 144 cells/mm3(g) and the median viral load was 43,190 copies/mL.

Study Showed Blunted Effect of a "Sequential" Triple-Drug Therapy

Further analysis from Study 035 presented today by Dr. Gulick showed that adding Crixivan to an existing two-drug regimen, AZT and 3TC, was not as effective as starting on triple therapy including Crixivan, AZT, and at least one other antiretroviral medication that patients had not previously taken, 3TC. Study 035 originally compared results of therapy with Crixivan alone, Crixivan in triple therapy with AZT and 3TC, and double-combination nucleoside therapy with AZT and 3TC. Patients taking Crixivan alone or AZT plus 3TC were switched to open-label triple therapy with Crixivan after 24 to 52 weeks. After 52 weeks of open-label triple therapy, only 13/29 (45%) of patients in this trial previously taking AZT and 3TC and 13/27 (48%) of patients previously taking Crixivan alone had viral levels below detection, compared to 22/28 patients (79%) of patients who started the study taking triple therapy with Crixivan.

"Delayed or sequential triple therapy produced more modest antiviral effects than initially starting drug therapy with a potent protease inhibitor and two nucleoside analogues," Dr. Gulick said. "This study suggests the need to begin treatment with triple therapy including a potent protease inhibitor because adding one protease inhibitor to a failing two-drug regimen of nucleoside analogues appeared suboptimal."

Published guidelines from the U.S. government and a leading international medical society recommend switching or starting at least two new antiretroviral agents when initiating therapy with a protease inhibitor. The combination of a potent protease inhibitor with two nucleoside reverse transcriptase inhibitors -- including triple therapy with Crixivan -- was recommended as a "preferred" treatment for established HIV infection, yet less than half of patients diagnosed with HIV worldwide are currently receiving this type of regimen. Guidelines for the use of antiviral agents were issued earlier this year by the U.S. Department of Health and Human Services' Panel on Clinical Practices for Treatment of HIV Infection(c) and the International AIDS Society.(d)

Crixivan Generally Well-Tolerated in Studies

Triple therapy with Crixivan was generally well-tolerated by patients in the two studies. In previous clinical trials, nephrolithiasis (or kidney stones) occurred with Crixivan in approximately four percent of patients. Adequate hydration is recommended in all patients treated with Crixivan. Ideally, Crixivan should be taken without food but with water one hour before or two hours after a meal. Alternatively, Crixivan may be taken with a light meal (low in calories, fat and protein). In post-marketing experience, some cases of nephrolithiasis have been associated with renal insufficiency or acute renal failure. In post-marketing experience with protease inhibitors, acute hemolytic anemia, hepatitis and hyperglycemia have been reported.

About Crixivan

Currently, more than 160,000 patients around the world are taking Crixivan, the world's most widely prescribed protease inhibitor. Crixivan is now approved in 65 countries and has been studied in more than 4,000 patients worldwide. Merck's U.S. catalog price for Crixivan is $12 per day ($4,380 per year), or 22 to 36 percent lower than the U.S. catalog price of other available protease inhibitors.(e)

Crixivan is the first drug to emerge from Merck's AIDS research program, which began in 1986 and led to breakthrough discoveries that became the basis for the development of protease inhibitors. Crixivan has been studied extensively by Merck, and dozens of studies testing Crixivan in new combinations, regimens, populations and strategies are ongoing or planned. Merck is also exploring basic research in many other areas of HIV/AIDS, including integrase inhibitors, chemokines and vaccines.

Merck (NYSE:MRK) is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative pharmaceutical products to improve human health.

Crixivan(R) is the Merck registered trademark for indinavir sulfate.

Full prescribing information for Crixivan follows.

Note: The "10" in "log10" is subscript. The "3" in "cells/mm3 is superscript.

* Footnotes:

* (a) Zidovudine (Retrovirr or AZT), Glaxo Wellcome

* (b) Lamivudine (Epivirr or 3TC), Glaxo Wellcome

* (c) Guidelines for Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, Federal Register, June 19, 1997

* (d) International AIDS Society Guidelines, JAMA. 1997; 277: 1962 - 1969.

* (e) Red Book, August 1997

* (f) The "10" in "log10" is subscript.

* (g) The "3" in "mm3" is superscript.

SOURCE Merck & Co., Inc.

Copyright (c) 1997/PR NewsWire. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Permissions Desk, PR Newswire, 810 Seventh Avenue, New York, NY 10019.
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