Graeme J. Moyle, MD, MBBS


February 06, 2000


Four hundred of the 900 patients at our AIDS clinic in Mexico are receiving Fortovase. We are considering using a dose of 1600 mg twice daily, rather than the recommended dose of 1200 mg three times daily, which may give us a small cost saving. What do you think about this decision?

Response from Graeme J. Moyle, MD, MBBS

The soft-gel capsule formulation of saquinavir (saquinavir-sgc; Fortovase) appears to be a generally well-tolerated protease inhibitor (PI) with, importantly, limited impact on lipids.[1] Small comparative studies comparing initial therapy regimens containing saquinavir-sgc versus indinavir or nelfinavir in tid regimens suggested similar activity over 1 year.[2,3] As with all PIs, it may be prudent to combine two PIs in regimens for experienced patients or those with high viral load (>100,000 copies/mL).[3]

Adherence studies suggest that adherence to medication is better for bid than tid dosing regimens. An adequately powered open-label study comparing 1200 mg tid and 1600 mg bid saquinavir-sgc plus nucleosides in treatment-naive and experienced patients has demonstrated equivalence in both activity and tolerability. Thus, the improved administration timing did not further increase the efficacy.[4] The cost saving associated with prescribing 2 fewer saquinavir-sgc capsules per day with the bid schedule would be around 11% of saquinavir-sgc costs per patient per day.

In practice, the decision to switch from tid to bid dosing for patients who are stable and responding to saquinavir-sgc (or indeed nelfinavir, which was also originally used tid and is now approved for bid use) should be assessed on an individualized basis taking account of personal factors and preferences. Clearly, if an individual has HIV RNA >50 copies/mL beyond 24 weeks of therapy, more than dosing adjustment will be required. While tolerability of bid dosing appears at least as good as tid, some individuals may find the larger pill volume difficult or may experience transient heartburn or loose stools following the change. If available, evaluation of the trough levels after 2 weeks of dosing may be of value: the target trough levels for saquinavir are >50-100 ng/mL. As exposure/response relationships are well established for PIs, inadequate levels of a PI would prompt either an increase in dose, addition of low-dose (100-200 mg/day) ritonavir (Norvir), or a change to a different agent.

Saquinavir-sgc can be combined safely with low-dose ritonavir. Once-daily dosing of this combination has been explored in pharmacokinetic studies; the combination of 1600 mg saquinavir-sgc with 100 mg ritonavir resulted in trough levels of saquinavir 4-5-fold above those achieved with standard dosing.[5] Data are lacking on bid dosing of saquinavir-sgc with low-dose ritonavir, but doses of 800-1200 mg saquinavir-sgc with 100 mg ritonavir bid are likely to provide substantial saquinavir exposure. Inclusion of ritonavir in the regimen may remove the food requirement for saquinavir-sgc administration and allows simultaneous dosing with didanosine, but may risk greater lipid disturbance and increase the range of potential clinically important drug interactions. There may also be modest cost advantage to this approach.

Other drugs which can be dosed once daily include didanosine (ddI, Videx), lamivudine (3TC, Epivir), efavirenz (Sustiva), and nevirapine (Viramune). Once-daily dosing may have advantages for a subset of patients who have difficulties with adherence.