Protease Inhibitors: SAQUINAVIR (INVIRASE™)

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

SAQUINAVIR (INVIRASE™)
Miklos Salgo, M.D., Ph.D.
Hoffmann-La Roche

Saquinavir (Invirase™) is the first protease inhibitor licensed via accelerated approval by the Food and Drug Administration (FDA). It has been extensively evaluated in multiple clinical studies of over 3,000 untreated and previously treated HIV-infected individuals.

In antiretroviral-naive people with baseline CD4 count fewer than 300 cells/mm³, saquinavir (1,800 mg per day) in combination with AZT (600 mg per day) induced a median HIV RNA decline of 1 log and a median CD4 increase of 70 cells/mm³ at 16 weeks. The maximum medium viral load decline with saquinavir/AZT was 1.6 logs after 2 weeks. At study entry, patients , on average, had CD4 counts of about 190 cells/mm³ and viral RNA of about 5.2 logs or 158,000 copies/mL.

In antiretroviral experienced people, saquinavir in combination with ddC produced a median HIV RNA decline of 0.6 log and a median CD4 increase of 30 cell/mm³ at 48 weeks. At baseline, patients, on average, had received prior AZT therapy for at least 1.5 years. Baseline CD4 counts ere about 160 cells/mm³ and viral RNA levels were about 5.3 logs or 200,000 copies/mL. Saquinavir was also evaluated in combination with AZT and ddC in 300 people with advanced HIV disease who had previously received AZT. On average, patients had received prior AZT therapy for 2 years; one-third of patients had prior ddC experience.

The triple combination of saquinavir plus AZT and ddC was associated with significantly better reductions in viral load and increases in CD4 counts than either of the two control combinations (saquinavir/AZT and AZT/ddC).

Maximum median HIV RNA decline of 0.8 log and maximum median CD4 increase of 35 cells/mm³ were observed with the triple combination at 8 weeks. However, both viral load and CD4 responses returned toward pre-treatment levels at 48 weeks. Overall, saquinavir in combination with AZT and/or ddC provided significantly better antiviral activity compared to similar treatment arms without saquinavir.

Saquinavir was well tolerated either alone or in combination with AZT and/or ddC. Clinical adverse events and laboratory abnormalities associated with saquinavir typically were mild and occurred at low incidence (see table 1 and 2). No increase in AZT- and/or ddC-related toxicities were seen when saquinavir was used in combination.

Table 1: Clinical Adverse Events
(Update of North America study)

% of patients with clinical adverse events related to study
drug* (moderate, severe, or life-threatening)

ddC SAQ SAQ + ddC

# of patients followed 145 159 147

diarrhea 1.4% 3.8% 3.4%

buccal mucosa ulceration 9.0% 2.5% 4.1%

headache 4.1% 0.6% 0.7%

peripheral neuropathy 5.5% 0.0% 4.8%

*In > 3% of patients in at least 1 arm.

Table 2: Marked Laboratory Abnormalities
(Update of North America study)

% of patients with marked laboratory abnormalities*

ddC SAQ SAQ + ddC

# of patients followed 145 159 147

CPK 6% 4% 7%

low glucose 4% 5% 4%

SGOT 3% <1% <1%

SGPT 3% <1% <1%

*Defined as at least a 3 Grade shift (ACTG Grading
System). In >3% of patients in at least 1 arm.

Based on these findings, saquinavir was licensed for the indication of its use in combination with nucleoside analogues for the treatment of advanced HIV infection in selected patients. Presently, there are no data from controlled clinical studies evaluating the activity of saquinavir in combination with nucleoside analogues other than AZT or ddC. Furthermore, there are no results available from clinical studies confirming the clinical benefit of saquinavir in combination with AZT and/or ddC on HIV disease progression or survival.

The recommended dose of saquinavir in combination with an approved nucleoside analogue is three 200 mg capsules three times daily taken within 2 hours after a full meal. Dr. Salgo cautioned that certain medications commonly use by people with HIV/AIDS, specifically rifampin and rifabutin, should not be taken with saquinavir since they have been shown to lower blood levels of saquinavir. In contrast, ketoconazole has been shown to increase saquinavir blood level.

Dr. Salgo also stated that studies with saquinavir in combination with antihistamines such as terfenadine (Seldane) or astemizole (Hismanal) have not been performed. Therefore, use of alternative antihistamines is recommended for now.

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

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