Efavirenz in plasma from HIV-infected patients does not directly block reverse transcriptase activity in cell-free assays but inhibits HIV replication in cellular assays.

The aim of this study was to characterize the potent nonimmunoglobulin (Ig) inhibitory activity defected in plasma from some HIV-infected, efavirenz (EFV)-treated patients. Concentration of EFV in plasma was measured by HPLC and correlation with reverse transcriptase (RT) inhibition or decrease in virus replication in cellular assays was searched. After plasma protein elimination by ethanol extraction, an inhibitory activity is measurable on RT in vitro that correlates with EFV concentration determined by HPLC. However, total plasma-containing EFV does not inhibit RT activity in cell-free assay, but it does efficiently inhibit virus replication in cell culture assays. Thus, despite being bound to plasma proteins (retention of EFV after extensive dialysis), EFV in plasma conserves its antiviral activity on infected cells. This observation precludes the use of crude sera and plasmas from EFV-treated patients for the study of antibody-mediated neutralizing activity.

Once-daily dosing of saquinavir soft-gel capsules and ritonavir combination in HIV-1-infected patients (IMEA015 study).

This was a prospective pilot study evaluating a saquinavir (SQV) soft-gel capsules (SGC)/ritonavir (RTV)-containing once-daily regimen over a follow-up of 3 months. The primary end-point was to determine the number of patients both remaining on treatment at month 3 and with trough SQV plasma concentration 24 h after the last intake (C24h) exceeding the inhibition of 95% of viral replication in vitro (IC95). The secondary end-points were to investigate the immuno-virological efficacy and safety of SQV-SGC/RTV once daily, and to explore SQV concentrations in peripheral blood mononuclear cells (PBMCs). Twenty-three antiretroviral-naive and 17 protease inhibitors (PIs) experienced HIV-1-infected patients with plasma HIV-1 RNA level below 200 copies/ml were enrolled. They were assigned to SQV-SGC/RTV (1600/100 mg once daily) combined with nucleoside and/or non-nucleoside reverse transcriptase inhibitors. In a subgroup of 13 patients, both plasma and intracellular SQV concentrations were determined. By intent to treat analysis the percentage of success at month 3 was 87.5% (confidence interval: 73.2-95.8%) with 78.3% in naive and 100% in PI-experienced patients. SQV C24h and intracellular concentrations [median (range, n)] were 241 ng/ml (40-1209, 35) and 323 ng/ml (168-475, 12), respectively. Intracellular concentrations showed an accumulation of SQV in PBMCs persisting during 24 h. Neither immunological nor virological failure was observed. Clinical and biological tolerance was acceptable in all patients but three with adverse effects leading to discontinuation. These data confirmed the short-term efficacy of SQV-SGC/RTV once-daily regimen based on SQV therapeutic drug monitoring.