Effectiveness

Saquinavir (Invirase) was approved after clinical studies demonstrated superior efficacy of saquinavir with ddC (zalcitabine, Hivid) over ddC or saquinavir monotherapy, and of saquinavir, AZT (zidovudine, Retrovir) and ddC over the dual nucleoside reverse transcriptase inhibitor (NRTI) combination of AZT and ddC.^{1 2}

Saquinavir was the first protease inhibitor to be commonly combined with low-dose ritonavir (Norvir) to boost drug concentrations and simplify dosing.^{3 4} The combination has been used as a salvage strategy since the late 1990s. Several studies have shown that between 40 and 70% of people who have failed another protease inhibitor-based regimen can achieve undetectable viral loads after six months’ treatment with a ritonavir-boosted saquinavir-based regimen, although previous exposure to antiretrovirals and levels of drug resistance, as well as adherence to therapy, play a crucial role in response to treatment.

Although one study has shown that ritonavir-boosted indinavir is a more potent salvage regimen than ritonavir-boosted saquinavir, ritonavir-boosted saquinavir causes fewer side-effects and has produced superior virological results after 48 weeks.⁵ However, following the publication of the results of the MaxCmin1 study, which demonstrated similar efficacy of ritonavir-boosted saquinavir and ritonavir-boosted indinavir, but with fewer side-effects in the saquinavir arm, British HIV Association (BHIVA) treatment guidelines have favoured ritonavir-boosted saquinavir or lopinavir (Kaletra) over ritonavir-boosted indinavir.⁶

Current United States and British HIV treatment guidelines recommend ritonavir-boosted protease inhibitors over single protease inhibitors in first-line therapy. However, more recently, ritonavir-boosted saquinavir has lost ground to Kaletra, with guidelines endorsing Kaletra as the preferred first-line protease inhibitor option. Importantly, the MaxCmin2 study found that people who took Kaletra were more likely than those who took ritonavir-boosted saquinavir to have undetectable viral load at 48 weeks. However, this was driven by fewer side-effects and better adherence in the Kaletra arm, rather than by the antiviral properties of the drugs themselves.⁷

The GEMINI trial, sponsored by Roche, is a 48-week open-label international study of SQV/r BID plus FTC/TDF QD compared to LPV/r BID plus FTC/TDF QD that enrolled over 300 antiretroviral naive patients. Twenty-four week data presented in July 2007 suggest that the drugs achieve similar virological suppression, but that saquinavir produces significantly fewer cases of raised lipids than does lopinavir.⁸

In an intent-to-treat analysis, the rate and extent of HIV-1 viral load reduction level were similar in both study arms. Undetectable viral load was reached by 70% in the LPV/r group vs 69% in the SQV/r arm. In each study arm, just over 81% had a viral load <400 copies/ml. Virological failure was observed in three patients (1.8%) receiving LPV/r and 10 patients (6%) receiving SQV/r. Most failures were adherence-related. Median CD4 cell count increase was also similar in both arms (LPV/r 135 vs SQV/r 127). Lipid changes and adverse events are noted in the Side-effects section of this entry.

Saquinavir is cleared from the body more slowly by women than men, so the drug reaches higher levels in the blood and brings about better virological responses in women.⁹ However, no differences in side-effects have been seen in clinical trials between men and women taking saquinavir. No dose adjustments are recommended, due to considerable inter-individual variability in drug concentrations.

Saquinavir does not penetrate the brain or semen to any significant extent, even when boosted with ritonavir.^{10 11}

Saquinavir is also active against the malaria parasite, which may be of relevance in areas where both HIV and malaria are endemic.¹²