Once-daily protease-based regimens

Simon Collins, HIV i-Base

Because of their more favourable half-lives, once-daily regimens have usually been studied using NNRTIs and nucleosides, and often in the context of IVDU-related adherence.

Many companies have recently initiated studies using currently available protease inhibitors boosted with ritonavir, to see if they could be used in once-daily dosing. None of these has produced particularly convincing results that this is either safe or to be recommended – even for a study period. Although once-daily regimens have advantages, the main drive for this research has been from a commercial and marketing perspective rather than a more favourable pharmacokinetic profile and/or improved safety. QD dosing of nelfinavir, saquinavir, indinavir or amprenavir, by co-administration with ritonavir increase susceptibility to toxicity through higher Cmax levels whilst retaining trough levels generally at best similar to standard Q12H or Q8H dosing.

A late-breaker poster looking at QD dosing of nelfinavir with ritonavir did not lead to inspiring results. Six combinations of the two PIs were compared to the standard 1250mg BID nelfinavir in a 14-day PK study in 73 HIV-negative volunteers – only one of which (2500 mg NFV/200 mg RTV) produced comparable trough levels (and a slight improvement on levels of NFV M8.

There were 10 discontinuations over the 14 days of the study. Five due to adverse events including rash, oral lesion (2), pruritus and neutropenia (including two people from the standard BID NFV control arm. Nausea and headaches were reported in 50% people in the 2500/200 arm, although, interestingly this was the only group that reported no incidence of diarrhoea (20-30% across other groups). Other reasons for discontinuation were not given.

In this study, ritonavir only appeared to have a moderate effect on nelfinavir AUC (13-44%) and on AUC NFV M8 (17-49%). Cmax approximately doubled compared to the control arm when 2500mg nelfinavir was combined with either 100mg or 200mg ritonavir. Although there is a likely QD PI in development (no data was presented on this drug by BMS at Durban on 232,632), developing dual-PI regimens that have greater flexibility (forgiveness) to approach true BID rather than Q12H regimens is likely to be more beneficial. It has also often been pointed out that where adherence is an issue, a missed QD dose presents a greater risk than one missed from a BID regimen.

An Italian study switched patients on an indinavir-containing regimen with undetectable viral load (<50 copies) to a once-daily regimen based on IDV 1200mg / RTV 100mg. While viral load didn’t rebound in the 12 patients evaluable at 16 weeks, 2/12 reported kidney stones, likely related to much increased peak IDV concentrations shortly after dosing.


  1. Hsyu P, Lewis R, Kerr B et al. Parmacokinetics (PK) of nelfinavir (NFV) after once daily dosing in combination with mini doses of ritonavir (RTV) in healthy subjects. XIII International AIDS Conference, Durban, July 9-14, 2000. Abstract LbPe7049.
  2. F Maggiolo, M Rizzi, G Finazzi – Once-a-day indinavir therapy in virologically controlled HIV+ persons XIII International AIDS Conference, Durban, July 9-14, 2000. Abstract TuPpA1155.

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