PRNewswire - Wednesday, December 16, 1998

"The complexity of antiretroviral combination therapy, as well as numerous side effects reported with protease inhibitors, make this type of regimen fine-tuning crucial," said Jeffrey Goodgame, M.D., Principal Investigator, Central Florida Research Initiative. "These studies indicate that adding Rescriptor to two different protease inhibitor combinations has an overall beneficial effect on viral load and CD4 cells, and they also address crucial adherence issues such as the need for simpler dosing schedules and lower doses of certain medications." Study 0063: Rescriptor in combination with reduced doses of indinavir result in decreased viral load

Investigators based their study of Rescriptor (DLV) on an earlier finding that concomitant use of Rescriptor with indinavir increases blood levels of indinavir two-fold. Pilot study 0063, Rescriptor (DLV, 400 mg) + zidovudine (also known as AZT or ZDV, 200 mg) + indinavir (IDV, 400 mg and 600 mg), was conducted to determine if reduced doses of indinavir could be taken in this combination while maintaining antiretroviral potency.

Forty-four NNRTI and protease inhibitor naive HIV-1 infected patients participated in this open label study. Participants were divided among three treatment arms:

Rescriptor (DLV 400 mg TID) + AZT (200 mg TID) + IDV (400 mg TID)

Rescriptor (400 mg TID) + AZT (200 mg TID) + IDV (600 mg TID)

AZT (200 mg TID) + 3TC (lamivudine 150 mg BID) + IDV (800 mg TID) - control arm

The participants' mean baseline CD4 cell count at the initiation of the study was 350 cells/mL and mean HIV RNA level was 4.9 log10.

After 24 weeks of therapy, 50-62 percent of patients in all three groups achieved HIV RNA below quantifiable levels (BQL) (<400 copies per/mL) using the Roche Amplicor assay and patients in all three groups demonstrated at least a 2 log10 decrease - or 41 percent decrease - in viral load.

An interim analysis of this study showed that patients in all three treatment arms achieved the following results (HIV RNA BQL): Rescriptor + AZT + IDV (400 mg) achieved 50 percent BQL, Rescriptor + AZT + IDV (600 mg) achieved 52 percent BQL and AZT + 3TC + IDV (800 mg) achieved 57 percent BQL.

Early CD4 cell increases were more than 100 cells/mL in all three arms and at 24 weeks all three treatment arms had achieved a median 130 cell/mL increase. All three regimens were well tolerated. The most commonly reported side effects were nausea (28 percent) and rash (18 percent). There were no grade 3 or grade 4 rashes reported.

Researchers from this multi-center study concluded that after six months of therapy, the two treatment regimens containing Rescriptor + IDV (400 mg) and Rescriptor + IDV (600 mg) have immunological and virological effects that are comparable to the standard regimen of AZT + 3TC + IDV (800 mg). Data from this pilot study formed the basis of a larger-scale study (protocol 0074) investigating these combinations that will be presented at the 6th Annual Conference on Human Retroviruses in Chicago, 1/31-2/4/99.

Study 0073: Twice daily dosing of combinations with Rescriptor result in decreased viral load

Researchers also presented results of an open label triple and quadruple combination study investigating twice daily (BID) dosing of both Rescriptor and nelfinavir (NFV). Eighty NNRTI and protease inhibitor naive HIV-1 infected patients were enrolled and randomized to one of four treatment arms:

Rescriptor (600 mg) + NFV (1250 mg) + d4T (stavudine 40 mg)

Rescriptor (600 mg) + NFV (1250 mg) + ddI (didanosine 200 mg) NFV (1250 mg) + ddI (200 mg) + d4T (40 mg)

Rescriptor (600 mg) + NFV (1250 mg) + ddI (200 mg) + d4T (40 mg)

Study participants had a median baseline viral load of 4.9 log10 and CD4 cell count of 356 cells/mL.

Antiretroviral results were rapidly achieved. The following results were observed across all drug regimens:

Within two weeks of initiating therapy, patients experienced a 1.2 log10 mean reduction on the Roche RNA PCR assay in viral load from baseline, or a 25 percent decrease.

After four weeks, patients experienced a 1.8 log10 mean reduction in viral load from baseline, or a 39 percent decrease.

After 12 weeks on therapy, participants in the three BID triple-drug arms had experienced at least a 2.5 log10 mean reduction in viral load from baseline, or 51 percent decrease, and those patients on BID quadruple therapy had a mean reduction of greater than 2.9 log10.

Overall, individuals had mean increases in CD4 cell count of 105-178 cells/mm3 across all four treatment arms.

All therapies were well-tolerated. The most commonly reported side effects were diarrhea (14 percent) and rash (10 percent). There were no grade 3 or grade 4 reported adverse events.

These study results suggest that twice-daily dosing of Rescriptor (600 mg BID) in combination with nelfinavir (1250 mg BID) plus d4T and/or ddI may result in a rapid and significant decrease in viral load within four weeks of initiating therapy. The changes in viral and immunological status seen in these patients suggest that these BID regimens are efficacious.

Rescriptor

Rescriptor, an NNRTI, received accelerated approval in the US on April 7, 1997.

It is also marketed in Brazil, Mexico, Argentina, Peru, Australia and Canada and marketing authorization applications have been submitted in the European Union and Switzerland.

Rescriptor tablets are indicated for the treatment of HIV-1 infection in combination with appropriate anti-retroviral agents when therapy is warranted. The indication is based on surrogate marker changes in clinical studies.

Rescriptor can be used to treat HIV-infected patients, including newly infected asymptomatic patients as well as those patients who have AIDS. Clinical benefit was not demonstrated for Rescriptor based on survival or AIDS-defining clinical events in a completed trial comparing Rescriptor plus ddI with ddI monotherapy. Rescriptor has been shown to be well tolerated. The most commonly reported side effect attributable to Rescriptor was a skin rash that occurred in 18% of patients. In most cases, the rash disappeared within three to 14 days without dosage reduction or interruption of treatment. In two pivotal clinical trials, 4.3 percent of patients treated with the recommended dose of Rescriptor discontinued treatment due to skin rash.

The recommended dose for Rescriptor is 400 mg, taken three times daily with or without food. Rescriptor should always be administered in combination with appropriate anti-retroviral therapy. The tablets are 100 mg each and are dispersible in water to make consumption easier. Pharmacia & Upjohn is a global, innovation-driven pharmaceutical and health care company. Pharmacia & Upjohn's products, services and employees demonstrate its commitment to improve wellness and quality of life for people around the world.

Rescriptor is a registered trademark of Pharmacia & Upjohn.

SOURCE: Pharmacia & Upjohn
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PR981206

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