Preliminary data from four studies of double PI regimen using once daily Fortovase plus “mini dose” ritonavir

Simon Collins, HIV i-Base

Roche announced on April 18 preliminary data from four ongoing studies examining the tolerability and antiviral activity of once-daily dosing of its protease inhibitor Fortovase (soft gel cap saquinavir) plus a “mini-dose” of a second protease inhibitor, ritonavir (Norvir), in addition to two nucleoside reverse transcriptase inhibitors (NRTIs).

The data were presented at the International Workshop on HIV Clinical Pharmacology (April 2-4, 2001, Noordwijk, The Netherlands. “The data from these Fortovase studies are early, but encouraging,” said Jonathan M. Schapiro, MD, Clinical Assistant Professor at the Stanford University School of Medicine and Director of AIDS Service at the National Hemophilia Center in Tel Hashomer, Israel.

“These studies with once-daily Fortovase plus ritonavir are in line with recent changes in US HIV treatment guidelines, which support the use of such ‘boosted’ protease inhibitor regimens as a means of possibly simplifying dosing regimens and thus improving adherence,” said Julio Montaner, MD, chair of AIDS research at St. Paul’s Hospital at the University of British Columbia in Vancouver and investigator in the FOCUS trial.

The FOCUS Trial

The FOCUS Trial is an ongoing study comparing the safety and efficacy of once-daily Fortovase (1,600 mg) in combination with 100 mg of ritonavir, along with two nucleoside reverse transcriptase inhibitors (NRTIs) vs. once-daily 600 mg efavirenz plus two NRTIs in treatment-naïve HIV-positive patients. Efficacy data are not yet available.

The data presented in The Netherlands focused on a pharmacokinetic (PK) sub-study of the FOCUS Trial evaluating a cohort of 49 patients. Six patients underwent an intensive PK profile and were evaluated for three parameters at week four, including Cmax at 24 hours (maximum concentration achieved), AUC 24h (“area under curve” or time curve from zero to 24 hours) and Cmin (lowest concentration in dosing interval). For these six patients, the median Cmax was 6,435 ng/mL. The AUC 24h was 66,920 ng-h/mL and the Cmin was 429 ng/mL.

Additionally, in the sub-study, a Cmin analysis of the entire cohort of 49 patients yielded a median Cmin of 376 ng/mL. In this study, the AUC24h and Cmin levels were higher than those previously observed for the current FDA-approved dosage of Fortovase. (The product labelling for Fortovase for 1,200 mg three times daily indicates an AUC8hr of 7,249 ng/mL. Previous trials have found a Cmin of 200 ng/mL.)

A preliminary safety analysis of 78 patients suggested no significant laboratory abnormalities during a treatment duration ranging from four to 24 weeks. The most frequently observed adverse events, from moderate to severe in intensity, included nausea (n=8), diarrhoea (n=4), vomiting (n=2) and headache (n=2). Five serious adverse events were reported. All were considered by the investigators to be unrelated to study medication.

The HIV-NAT 001.3 Trial

Sponsored by the HIV Netherlands Australia Thailand Research Collaboration, HIV-NAT presented 24-week data on 66 patients with HIV RNA of <50 copies/mL who switched from twice-daily Fortovase (1,400 mg) as the sole protease inhibitor to once-daily Fortovase (1,600 mg) plus ritonavir (100 mg). At week 24, 100 percent of patients on treatment (n=64) remained below 400 copies/mL and 92 percent of patients on treatment (n=61) maintained a plasma viral load below 50 copies/mL. The median CD4 cell count increased by 157 cells after 24 weeks.

Adverse events occurring in at least four patients included nausea (n=5) and elevations in triglycerides (n=6) and SGTP (n=4). No patients discontinued due to toxicity.

The IMEA 015 Trial

The IMEA 105 Trial evaluated virological and immunological results for once-daily Fortovase (1,600 mg) plus ritonavir (100 mg) in 35 patients. The patients were either PI-naïve with HIV RNA of >10,000 copies/mL and CD4 counts ranging from 50 to 500, or PI-experienced with HIV RNA <200 copies/mL. Among PI-naive patients, viral load decrease was -2.70 log10, and among PI-experienced patients, viral load remained below 200 copies after 12 weeks. The average CD4 increase among PI-experienced patients was 56 after 12 weeks, and among PI-naïve patients, 83.

Fortovase plus ritonavir was well tolerated in this trial. Three patients with severe adverse events not related to treatment discontinued participation in the trial. The discontinuations reported were: one for gastrointestinal disorders, one for pregnancy and one lost contact.

Spanish Once-Daily Fortovase Trial

Twelve-week data from a study examining patients switched to once-daily Fortovase plus ritonavir after failing an Invirase (hard gel cap saquinavir)-based HAART regimen were also presented at the conference. This study examined 14 patients over 12 weeks, including four with the L90M mutation at baseline, which is usually associated with saquinavir resistance.

Fortovase Adverse Events, Cautions and Warnings

The most frequently reported adverse events at least possibly related to treatment with Fortovase and of at least moderate intensity – observed in trials evaluating a 1,200 mg three-times-daily dosing regimen – include nausea (17.8 percent), diarrhoea (15.6 percent), abdominal discomfort (13.3 percent) and dyspepsia (8.9 percent).

Fortovase should not be co-administered with astemizole, terfenadine, ergot derivatives, cisapride, midazolam or triazolam, due to the potential for serious and/or life-threatening events. Concomitant use with lovastatin or simvastatin is also not recommended.

Caution should be exercised with other HMG-CoA reductase inhibitors metabolised by the CYP 3A4 pathway. Exacerbation of chronic liver dysfunction has been reported in patients treated with Fortovase. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.

There have also been reports of hyperglycaemia, new onset or exacerbation of diabetes and of spontaneous bleeding in patients with haemophilia. Please refer to the complete product information for detailed safety information for Fortovase.

The extensive drug-drug interactions and cautions associated with the use of ritonavir should also be exercised even if this agent is administered in 100mg dosages.

Complete Fortovase prescribing information

Source: Roche Laboratories.


Comparisons with more clinically relevant combinations could be made between these once daily regimens and FTV 600mg / RTV 400mg bid regimen (for which clinical efficacy data do exist) and a FTV 1000mg / RTV 100mg bid arm (which is clinically often used).

This approach may have the additional benefit to validate preliminary data suggesting that RTV 100mg may be sufficient to boost Fortovase and that higher doses of ritonavir may not have any additional PK enhancing effects.

Fortovase without a ritonavir booster is now a rarely used regimen due to high pill burden and tid dosing.

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