HIV POSITIVE Treatment
Proceedings to the Community Symposium on
Protease Inhibitors: Current and Future Use
By Jules Levin, Executive Director of NATAP

NELFINAVIR (VIRACEPT™)

Sharon Chapman, Ph.D. Agouron Pharmaceuticals

Nelfinavir (ViraceptTM or AG1343) is a potent HIV protease inhibitor with ED95 of 40 ng/ml. It is active against a variety of HIV strains including AZT-resistant and pyridinone-resistant clinical isolates in different cell types. The compound has been shown to achieve statistically significant synergistic interactions in combination with AZT, ddC, or 3TC under an acute infection condition (HIV-1 RF/CEM-SS) in cell culture. Nelfinavir also showed additive interactions with a trend toward synergy when combined with either ddI or d4T in cell culture. Furthermore, results from a three-way combination study revealed detection of statistically significant synergistic interaction with nelfinavir in combination with AZT and 3TC.

Drug resistant laboratory studies were conducted by Drs. David Ho and Martin Markowitz at the Aaron Diamond AIDS Research Center to assess whether viruses become less sensitive to drug inhibition with prolonged exposure to nelfinavir. Indeed, nelfinavir resistant viruses were detected after 28 rounds of serial passage of wildtype (or drug sensitive) virus in the presence of increasing amounts of the drug. The resistant viruses were 30-fold less sensitive to nelfinavir as compared to the parental wildtype virus. Two mutations were associated with the reduced sensitivity to nelfinavir (at codons 46 and 84).

To address the issue of potential cross-resistance, recombinant viruses containing one or more primary resistance mutations associated with saquinavir, indinavir and ritonavir were constructed and evaluated for their sensitivity to nelfinavir. While the single mutated viruses were 1- to 5-fold less sensitive to nelfinavir, none were considered to have any relevant impact toward triggering cross-resistance to other protease inhibitors. A 10-fold change in drug sensitivity is usually considered relevant.

Dr. Amy Patick of Agouron at the Drug Resistance Workshop in Whistler in July reported new findings on the resistance profiles in nelfinavir-treated patients.

Several pilot phase II studies have been performed in both U.S. and U.K. to assess the safety, pharmacokinetics, and optimal doses and activities of nelfinavir in over 100 HIV-infected individuals (see table 4 below).

Participants received doses of nelfinavir capsules or tablets ranging from 770 mg to 3,000 mg per day. Twice daily regimens of nelfinavir have induced median maximum reduction of about 1.5 log in viral load. With increasing doses of thrice daily regimens, median maximum viral load decline reached over 2 log. Fifty to sixty percent of patients receiving 2,250 mg or 3,000 mg per day achieved levels of HIV RNA below the limit of detection (< 500 copies/ml) after 4 weeks. Nelfinavir was generally well tolerated in all patients with mild to moderate gastrointestinal disturbances being the most common adverse event.

Table 4: Nelfinavir Pilot Phase II Program
Patient Daily Dose (mg) Formulation Regimen Site
10 770 capsule 3x U.K.
10 1,030 capsule 2x U.K.
10 1,000 tablet 2x U.S.
10 1,200 tablet 2x U.S.
15 1,500 tablet 2x U.S.
10 1,500 tablet 3x U.S.
10 2,250 tablet 3x U.S.
10 3,000 tablet 3x U.S.
10 d4T+1,500 tablet 3x U.S.
10 d4T+2,250 tablet 3x U.S.
10 d4T+3,000 tablet 3x U.S.
10 d4T -- -- U.S.

An ongoing pilot study is now evaluating nelfinavir in combination with d4T in 40 HIV-infected individuals. Study participants were randomized to receive one of three daily doses of nelfinavir tablet (1,500, 2,250, or 3,000 mg) in combination with d4T or d4T monotherapy.

Clinical experiences based on patients who had switched from nelfinavir monotherapy to combination therapy have shown that persistent viral suppression can be achieved following initial rebound of viral load. For example, one patient (#03-06), who entered the study with a baseline viral load of 350,000 copies/ml, responded to nelfinavir monotherapy with an initial peak viral load decline of over 1.5 logs which subsequently was returned toward baseline level after 3 months. However, once AZT was combined with nelfinavir at month 3, the patient then achieved a profound decline in viral load of over 3 logs or below the limit of detection.

Dr. Chapman explained that the extent of demonstrable viral load suppression is solely dependent on the baseline viral load value of the individual. If one begins antiretroviral therapy with low viral load, one is expected to quickly surpass the ability of viral load test to detect changes. A total of 6 phase II/III controlled studies of nelfinavir in over 1,000 HIV-infected people entered the clinics in early 1996. A preliminary synopses of the design of these studies are the following (note: these studies have been ongoing since February 1996 and some have been modified):

This document was written by Jules Levin, Executive Director of NATAP

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