Glasgow, UK, 23 October, 2000 - Roche has announced the results of in vitro laboratory experiments showing that the Roche HIV protease inhibitor (PI) saquinavir is more potent than the new PI, lopinavir.

The study, presented at the 5th International Congress on Drug Therapy in HIV Infection in Glasgow, tested the potency of the two drugs side by side in the laboratory in the presence of the key blood plasma protein alpha 1 acid glycoprotein. Both saquinavir and lopinavir were tested against a number of different HIV mutants, characteristic of viruses found in patients for whom protease therapy has failed, as well as the wild-type virus. The purpose of the experiments was to determine which drug had the higher potency against each viral strain. The results showed saquinavir to be more potent than lopinavir against wild-type HIV and also a range of drug-resistant viral strains with the exception of one virus containing both the G48V and L90M mutations.1

"This study is the first step towards making direct comparisons between two protease inhibitors in the same laboratory across a variety of conditions," said Dr. Cammack, Roche Research’s HIV Disease Area Head, Welwyn, UK. "Whilst these laboratory data are extremely encouraging, we know that other variables also have an impact on a drug’s activity in a clinical setting, therefore we now need to move closer to the real world by conducting head-to-head clinical trials in patients infected with HIV.”

The results reported by the Roche team are important as they come at a time of revolution for the HIV protease inhibitors - the drugs that changed the face of HIV treatment. Results from a number of studies reported over the last couple of years show that plasma levels of the protease inhibitors can be elevated by the addition of a small amount of ritonavir - itself a protease inhibitor.2,3,4
In an attempt to determine which boosted protease inhibitor is more clinically efficacious, Roche is supporting a collaborative group (Copenhagen HIV Program) to undertake a head-to-head clinical study comparing two boosted PIs.  This is the first trial of its kind and compares the safety and efficacy of Fortovase (saquinavir SGC; 1000mg BID) combined with low doses of ritonavir (100mg BID) versus indinavir mesylate (800mg BID) also boosted with low doses of ritonavir (100mg BID). "While the protease inhibitors have been in widespread use for around 5 years the practice of boosting PI levels using ritonavir is quite new. When used in this way the PIs are behaving like new drugs. There is an urgent need for head-to-head studies comparing the various boosted PIs so we can work out how best to use these new treatment options," said Dr. Lundgren, Hvidovre Hospital, Copenhagen.

"Our results fill in part of a puzzle," commented Dr. Cammack, Roche Research’s HIV Disease Area Head, Welwyn, UK. "The five years since the PIs were launched have taught us many things. Perhaps the most sobering is that the virus is unforgiving. If there is an opportunity for it to mutate and escape - then it will. We need to use the most potent drugs possible and use them at concentrations that overwhelm the virus without causing undue toxicity. The data we are seeing with saquinavir both in the laboratory, where we try to mimic the protein binding effects that the drug would meet in human plasma, and in our clinical studies where it is combined with low-doses of ritonavir, indicate that saquinavir is challenging the virus on both fronts." 

1. Craig, C et al. Antiviral efficacy and effects of protein binding on HIV proteinase (PR) inhibitors (PI). Abstract 290. 5th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 22-26 October 2000.

2. Kilby, J M et al. Safety and Pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus negative adults. Antimicrobial Agents and Chemotherapy 2000; 44(10): 2672-2678.

3. Saah A et al. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) and ritonavir (RTV) combinations in a once-daily regimen in healthy volunteers (Merck 089), Abstract 329, 39th ICAAC, San Francisco, US, 26-29 September 1999.

4. Sham HL et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrobial Agents and Chemotherapy 1998; 42(12): 3218-3224.