The current role of ritonavir-boosted protease inhibitors in the management of HIV infection.

AuthorWilkins, Ed
PositionLEADING ARTICLE - Report


Adramatic decline in clinical progression and HIV-related deaths followed the introduction of the protease inhibitor (PI) class of antiretrovirals in 1995. Protease inhibitors act by mimicking the natural substrates of the HIV protease enzyme, interfering with assembly of new virus by inhibiting post-translational protein cleavage. Early data on initial therapy demonstrated potent but transitory antiviral effect with ritonavir and indinavir monotherapy and was followed by several seminal papers evaluating a regimen consisting of a PI combined with two nucleosides designed for maximal suppression of HIV replication [1]. Even without boosting, protease inhibitors have a higher genetic barrier to resistance than the other main classes with mutations appearing sequentially with a stepwise increase in resistance over time. ACTG 229 compared saquinavir, zidovudine (ZDV) and zalcitabine with ZDV combined with either saquinavir or zalcitabine. ACTG 320 and Merck 035 compared indinavir, ZDV and lamivudine to ZDV/3TC dual therapy (Merck 035 also evaluated indinavir monotherapy) [2,3]. All three studies demonstrated the significant added virological benefit of a three-drug combination therapy with sustained suppression leading to a superior CD4 cell count elevation and reduction in the development of emergent resistance to any of the individual components. The durability of this regimen strategy was further borne out in Merck 035 with ontreatment analysis revealing sustained virological suppression over 5 years in many patients [3]. Following this, saquinavir, ritonavir, indinavir and nelfinavir all received approval for use by 1997.

Soon after the introduction of PIs it was recognised that co-administration with ritonavir improved their pharmacokinetic profile. Initial data on boosted PIs came from studies of dual therapy with ritonavir and saquinavir at therapeutic doses that demonstrated that this was an effective and durable alternative for maintaining viral suppression when given alone or with one or two NRTIs [4]. The dose of ritonavir in boosted regimens (100-200mg) is generally considered subtherapeutic but through hepatic and intestinal CYP3A4 inhibition, it reduces the metabolism of the concomitantly administered PI and changes the pharmacokinetic parameters with increases in the area under the curve (AUC) and [C.sub.min] resulting in increased drug bioavailability. This allows for reduced pill burden, fewer food and drink restrictions and a lower dosing frequency thereby improving adherence, while higher plasma concentrations provide for greater activity against resistant virus and a reduced likelihood for its development. For certain PIs such as tipranavir, lopinavir and darunavir, boosting with ritonavir is an obligatory requirement to achieve therapeutic levels. All guidelines now recommend boosted PIs in all contexts when a PI is considered excepting where there are real risks of complications from the ritonavir component.

For the purposes of this review of boosted PIs, monotherapy, switch, and dual boosted PI studies are not considered.



Indinavir was one of the first four first-generation protease inhibitors. It is now rarely used as it is handicapped by its narrow therapeutic window, particularly the tendency for nephrolithiasis, which is increased when boosted drug is used. Early open dual PI studies of indinavir/ritonavir 400/400mg with two NRTIs confirmed its efficacy in naive patients and comparative evaluation of twice-daily boosted indinavir 800/100mg to unboosted indinavir dosed thrice daily 800/100mg demonstrated equipotency and allowed relaxation of the requirements for fasting. The ADVANZ study compared boosted indinavir with efavirenz in 100 patients with a CD4 cell count


Indinavir is now infrequently prescribed in the UK although it remains a valuable PI. Relative to other PIs it is less potent and its boosted use is associated with more toxicity. Hence, there has been no definitive evaluation of its comparative efficacy and safety with boosted lopinavir or another boosted first-line PI and this is unlikely to happen.


Recent research has demonstrated that a lower boosted indinavir dose (400/100mg) retains potency and is considerably less toxic. Given the relative cost of protease inhibitors, indinavir remains a cheap option and there is therefore interest in its application in resource-poor settings.



Saquinavir, which in its original form was a 200mg hard gel capsule, has undergone reformulation twice to improve initially bioavailability (to a 200mg soft gel capsule) and subsequently to increase tolerability and reduce pill burden (to a 500mg tablet). Unboosted saquinavir has poor bioavailability and requires ritonavir boosting. Boosted saquinavir has demonstrated potency in once- and twice-daily schedules. In the Max[C.sub.min]1 trial, boosted saquinavir was compared to boosted indinavir both dosed twice daily, where 25% of patients were treatment-naive, 14% treatment-experienced but PI-naive, and the remainder PI-experienced. By the protocol-defined primary endpoint of time to virological failure, saquinavir was superior to indinavir with a greater number of treatment-limiting adverse events. The Max[C.sub.min]2 trial compared boosted saquinavir with boosted lopinavir again both dosed twice daily in patients where one-third were naive and 52% PI-experienced [7]. At 48 weeks, treatment failure (defined as a composite endpoint of observed virological failure, withdrawal of consent, loss of patient to follow-up, and death) occurred in 18% of those in the lopinavir arm and in 33% of those in the saquinavir arm. Much of the difference was driven by an increased number of discontinuations for 'patient's choice' in the saquinavir arm suggesting adherence played a part.


In a randomised open-label two-arm non-inferiority Phase IIIb study ritonavir-boosted saquinavir dosed 1000/100mg was compared against ritonavir-boosted lopinavir both dosed twice daily (the GEMINI study) together with fixed-dose emtricitabine and tenofovir [8]. Patients with CD4 cell counts 10,000 copies/ml were randomised 1:1 with the primary endpoint being the proportion of patients with a viral load


No recent large-scale randomised trial has evaluated boosted saquinavir against another third agent in experienced patients although it has been assessed as a second PI/boosting agent in BMS-045 as well as other double PI combinations [9]. ACTG 389 compared boosted saquinavir, boosted indinavir, nelfinavir and placebo all dosed twice daily in a large randomised study [10]. Primary efficacy endpoint was the proportion of persons with viral loads


Several small studies of once-daily boosted saquinavir using the early formulations at varying doses but mainly 1600/100mg have demonstrated...

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