Studies continue to support the effectiveness, durability, and ease-of-use of FORTOVASE^® (saquinavir). New data on FORTOVASE were presented at the 7^th European Conference on Clinical Aspects and Treatment of HIV-Infection in Lisbon.

Data from a study in HIV-positive patients demonstrated that FORTOVASE 1600-mg plus ritonavir 200-mg in a new once-a-day (or QD) regimen resulted in therapeutic levels of saquinavir throughout the dosing interval; these data were supported by data from a QD study in healthy volunteers.

Additional data supporting FORTOVASE twice-a-day (BID) dosing, and the effectiveness of FORTOVASE in preventing transmission of HIV from mother to child were reported at the conference. Data confirming FORTOVASE efficacy, safety and durability of response out to 96 weeks were also presented.

FORTOVASE Once-a-Day

Data presented by Richard Hoetelmans, MD¹, from the first pharmacokinetic (PK) study in HIV-positive individuals to evaluate the once-a-day dosing of FORTOVASE 1600-mg plus ritonavir 200-mg showed that therapeutic concentrations of FORTOVASE were maintained over the course of 24 hours.

Seven HIV-positive individuals who were being treated with INVIRASE 400-mg twice a day (BID) plus ritonavir 400-mg BID were switched to a regimen of FORTOVASE 1600-mg QD plus ritonavir 200-mg QD. Plasma levels of FORTOVASE, ritonavir, HIV-1 RNA and fasting cholesterol, HDL, LDL, and triglyceride levels were all measured on day 0 and day 14.

Of the four patients who have completed the study thus far, the median pharmacokinetic parameters were AUC_[0-24] 19.9 h*m g/ml, C_max 3.2 m g/ml, C_min 0.14 m g/ml, and T_½ 7.5 h. No significant changes were observed in cholesterol, HDL, and LDL levels. Triglyceride levels decreased from 3.1 mmol/l on day 0 to 2.3 mmol/l on day 14. Many researchers believe that triglyceride and cholesterol elevations and other lipid abnormalities may be early indicators of problems like lipodystrophy (the redistribution of body fat associated with some anti-HIV medications), and premature cardiovascular disease.

All patients in the study maintained viral suppression (<400 copies/mL) while on the QD regimen. The regimen was well-tolerated with no serious adverse events reported.

These data suggest that this combination of FORTOVASE 1600-mg QD plus ritonavir 200-mg QD provides therapeutic levels of FORTOVASE in a convenient once-daily dosing in people living with HIV. The authors recommend continued clinical evaluation of this regimen.

Michael Saag, MD², of the University of Alabama – Birmingham, presented data from a study of healthy volunteers to evaluate the pharmacokinetics of mini-dose ritonavir with FORTOVASE and their interaction with ddI. Pharmacokinetic parameters (geometric mean) of the study are summarized:

These data suggest that the addition of ritonavir 100-mg QD to FORTOVASE 1600-mg QD increased the exposure over the 24-hour dosing interval of FORTOVASE 7-fold versus the standard TID regimen. The key PK variable of C_min at the end of the 24-hour dosing interval was 450% higher compared to standard TID dosing.

Adding ddI to the QD regimen did not appear to cause any interactions. There were no significant adverse events or abnormal laboratory values. These data suggest that the FORTOVASE 1600-mg QD plus ritonavir 100-mg QD is a promising regimen for evaluation in people living with HIV.

The Long-Term Safety, Efficacy and Durability of FORTOVASE (M61025)

Data presented by Dr. Margaret Johnson, UK³, from long-term FORTOVASE studies show the efficacy, durability and tolerability of FORTOVASE containing combination regimens out to 96 weeks of therapy, as well as which factors appear to be predictive of a long-term response.

Subjects who were enrolled in either the NV15355 study or the SPICE study and who had completed at least 72 weeks of therapy and had HIV RNA levels < 400 copies/ml for the last 24 weeks were eligible to rollover into M61025 while continuing their regimen.

The data show that triple therapy with FORTOVASE + 2 nRTIs provides a durable virologic response to 96 weeks and that CD4 cell counts continue to rise, suggesting continued immunologic improvement. Quadruple therapy was associated with a significantly longer time to relapse⁴, while response to dual therapy showed a shorter time to relapse. No adverse events emerged by week 96.

In addition, analysis of the differences between long-term responders and non-responders suggests that achieving rapid and early response to therapy is predictive of long-term response. Dr. Johnson reported that rapid suppression of HIV RNA (<400 copies/ml by week 12 and < 50 copies/ml by week 16) appear to be consistent predictors of a durable response.⁵

The study indicates that use of early and intensive viral load monitoring can help identify patients with low likelihood of response to treatment. This information will allow physicians to modify treatment early, potentially allowing more successful treatment outcomes for patients.

The TIDBID Study (M61018)

The body of data on twice-daily FORTOVASE dosing continues to grow. In a large, prospective, on treatment 48-week analysis, 169 patients were studied in three groups: those receiving FORTOVASE 1600-mg BID + 2 NAs, FORTOVASE 1200-mg BID + VIRACEPT 1250-mg BID + 1 NA or FORTOVASE 1200-mg TID + 2 nucleoside analogues (NAs).

Cohort data presented by P. Carey⁶ at week 48 are summarized in the table below:

These data show that BID regimens containing FORTOVASE with or without VIRACEPT provide potent HIV suppression, tolerability, and safety.

Results From Two Genotype and Phenotype Studies

C. Craig, MD, presented data from two studies of genotypic and phenotypic resistance analysis to FORTOVASE and FORTOVASE plus VIRACEPT regimens.

The first study⁷ reviewed subjects enrolled in the NV15355 study comparing the two formulations of saquinavir (FORTOVASE vs. INVIRASE) in order to determine whether the different formulations might generate different drug resistance profiles. Of the 102 subjects on the virology substudy, 37 were evaluable; 33 were genotyped and 30 were phenotyped. Key saquinavir resistance mutations and drug sensitivity to saquinavir are summarized:

One sample showed significant phenotypic resistance to saquinavir (16-fold), with similar resistance to ritonavir and intermediate resistance to indinavir and VIRACEPT. Six subjects had changes at the gag cleavage site. Most subjects (29/33) had received 3TC and 16 of the INVIRASE subjects and 9 of the FORTOVASE subjects had high level resistance to 3TC. Six subjects had mutations suggesting resistance to both AZT and 3TC.

However, resistance to saquinavir was uncommon after 48 weeks of therapy, with the researchers suggesting that the gag cleavage site mutations were either polymorphic or of unclear influence.

The other study Craig presented⁸ reviewed data from the dual PI study NV 15436, two arms of which had subjects who received FORTOVASE plus VIRACEPT. Thirty-four subjects were evaluated, ten receiving FTV +NFV + 2 nRTIs and 24 receiving only FTV + NFV. Of those on quadruple therapy, no phenotypic changes were found. In the other arm, two subjects had phenotypic resistance to NFV and six others had dual phenotypic resistance and resistance levels to NFV were greater than to FTV. The only key resistance mutation observed was 90M – two in the quadruple arm and seven in the dual arm; it was present in all NFV resistant subjects and in all but one of the dual resistant subjects.

The researchers conclude that 90M is the preferred resistance mutation selected for during FTV + NFV therapy and it often preempted phenotypic resistance. Phenotypic resistance also correlated well with the presence of 90M, while gag cleavage site mutations did not correlate with resistance.

Favorable FORTOVASE Profile Shown In Comparative Data on Metabolic Markers

The following study looked at the degree to which FORTOVASE may impact triglycerides and other markers to help physicians and patients make informed decisions regarding treatment options.

Dr. A. Wensing⁹ presented data from a small (n = 17) prospective study that examined the metabolic and virologic effects of switching from a ritonavir-containing combination regimen to one containing either FORTOVASE + VIRACEPT (nelfinavir) or VIRACEPT with no change in the underlying nucleoside analogues (NAs) on patients whose virus was suppressed. This study was intended to provide an option for patients on ritonavir-based regimens during the 1998 Abbott/ritonavir manufacturing crisis and subsequent ritonavir-capsule formulation withdrawal.

At week 24, viral load remained undetectable and CD4 counts remained stable in both arms of the study. In addition, mean triglyceride levels decreased from 4.42 to 2.27 mmol/l (p = 0.003) in both arms. GGT levels also declined from a mean of 178.17 units/l at baseline to 102.58 units/l (p = 0.02).¹⁰

1. van Heeswijk RPG et al. The steady-state pharmacokinetics of saquinavir in a once daily dosing regimen with a low dose of ritonavir.
2. Saag MS et al. Modulation of saquinavir steady-state pharmacokinetics with ‘baby’ doses of ritonavir in healthy volunteers.
3.Staszewski S (M. Johnson) et al. Durability of response to combination therapy with saquinavir-soft gelatin capsules (SQV-SGC).
4.Lazzarin A et al. FORTOVASE^® (FTV) or FTV + NFV BID plus NA(s) regimens compared to FTV TID regimen in HIV-1 infected patients.
5. Staszewski S (M. Johnson) et al. Durability of response to combination therapy with saquinavir-soft gelatin capsules (SQV-SGC).
6. Craig C (P. Carey) et al. Genotype and phenotype analysis of HIV gag, proteinase (PR) and RT during therapies with saquinavir (SQV).
7. Craig C (P. Carey) et al. Genotype and phenotype analysis of HIV gag, proteinase (PR) and RT during therapies with saquinavir (SQV).
8. Craig C (P. Carey) et al. HIV-1 genotype and phenotype during dual PI therapy (NV15436 sub-study).
9. Wensing AMJ et al. Switching ritonavir as part of triple therapy to nelfinavir or to saquinavir SGC/nelfinavir results in continued viral suppression.
10. Normal is 9-85 units/l. See: Tierney LM Jr., McPhee SJ, and Papadakis MA, eds. Current Medical Diagnosis & Treatment 1998. Stamford, CT: Appleton & Lange, 1998. Page 1533.