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


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 <100 cells/[mm.sup.3] and did not reveal any significant differences but did not support the then widely held belief that boosted PIs were beneficial in patients with low CD4 counts [5]. The Max[C.sub.min]1 study compared boosted indinavir with boosted saquinavir in a mixed population both dosed twice daily [6] (see below).


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 <350 cells/mm3 and viral loads >10,000 copies/ml were randomised 1:1 with the primary endpoint being the proportion of patients with a viral load <50 copies/ml at 48 weeks. Median baseline viral load and CD4 cell count were 138 cells/[mm.sup.3] and 5.2 [log.sub.10], respectively. In total, 337 patients were recruited and non-inferiority was demonstrated at 48weekswith 64.7%of those taking boosted saquinavir and 63.5% of those taking boosted lopinavir achieving a viral load <50 copies/ml. Discontinuations for virological failure and adverse events were 7% and 3% for boosted saquinavir and 3% and 7% for boosted lopinavir. Adverse effects were mainly gastrointestinal (27% of those taking boosted lopinavir vs. 17% of those taking boosted saquinavir) with the difference mainly being due to higher rates of grade 3-4 diarrhoea in the lopinavir arm. Significantly higher triglyceride elevations were also seen with boosted lopinavir. One poorly adherent patient receiving boosted saquinavir developed new major PI mutations.


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 <200 copies/ml at 24 weeks. Results revealed no advantages of one PI over another although all were more active than placebo and the use of two PIs and an NNRTI in an NNRTI-naive patient was associated with a better outcome. The need for boosted saquinavir in a PI-experienced patient is now going to be infrequent with the advent of PIs demonstrating greater activity against resistant virus in vitro.


Several small studies of once-daily boosted saquinavir using the early formulations at varying doses but mainly 1600/100mg have demonstrated variable results. In the FOCUS study, boosted saquinavir dosed 1600/100mg was compared to efavirenz but demonstrated inferior results (51% on boosted saquinavir compared to 71% on efavirenz at 48 week had viral undetectability at <50 copies/ml) [11]. The SPRINT study compared boosted daily saquinavir dosed 1600/100mg against boosted twice-daily indinavir in PI-naive persons and demonstrated equipotency (51% of those receiving boosted saquinavir and 43% of those receiving boosted indinavir had viral loads <50 copies/ml) [12]. In another single-arm open study (STACCATO), 200 patients with CD4 cell counts between 200 and 350 cells/[mm.sup.3] received boosted saquinavir once daily dosed 1400/100mg. After 24 weeks of treatment, 89% had viral loads below 50 copies/ml with a median rise in CD4 cell count of 122 cells/[mm.sup.3] [13]. Once-daily studies are now underway utilising the 500-mg tablet formulation and will report in the near future. Because of its compatible pharmacokinetics with both lopinavir and atazanavir, saquinavir has been studied as an agent in dual PI studies.



The therapeutic effect of different doses and schedules were assessed in a double-blind randomised study of boosted lopinavir (study M97-720) in naive patients with stavudine and lamivudine following which the twice-daily dose of 400/100mg was chosen [14]. At 48 weeks, patients had viral loads of <50 copies/ml and mean CD4 cell count increases of 213 cells/mm3. Seven-year data confirmed the durability and continued efficacy of this regimen with 67% of patients maintaining viral undetectability.


Study M98-863 was a double-blind randomised placebo-controlled evaluation of twice-daily boosted lopinavir with unboosted thrice-daily nelfinavir 750mg in patients who also received non-blinded stavudine and lamivudine twice daily [15]. The study heralded the benefits of the principle of boosting with ritonavir. The primary efficacy endpoints were the proportion of individuals with viral loads <400 copies/ml at 24 weeks and the time to loss of virological response through 48 weeks. Baseline viral load was 5.0 log10 and CD4 cell count 232 cells/mm3. Of the 653 naive patients, 75% and 67% of those randomised to receive boosted lopinavir compared to 63% and 52% of those receiving nelfinavir had viral loads <400 copies/ml and <50 copies/ml at 48 weeks, respectively. Time to loss of virological response was greater in the lopinavir group (HR 2.0: 95% confidence intervals 1.5-2.7) with both regimens being well tolerated (3.4% of those receiving lopinavir vs. 3.7% of those on nelfinavir discontinued for adverse effects). Additionally, patients randomised to boosted lopinavir who developed virological failure had no evidence of primary PI resistance. Having established itself as the gold standard in naive patients for other boosted PIs to be compared to, subsequent and separate head-to-head comparisons have taken place with other boosted protease inhibitors. These include boosted atazanavir (the CASTLE study), boosted darunavir (the ARTEMIS study), boosted fosamprenavir (the KLEAN study), boosted saquinavir (the GEMINI study) and boosted tipranavir (BI1182.33) [8, 16-19]. These are discussed individually in the section of the comparator PIs but have generally confirmed the lack of emergent primary PI resistance in boosted PI combination therapy as well as consolidated the position of lopinavir as a potent first-line PI for naive patients. The main adverse effects are dyslipidaemia, particularly hypertriglyceridaemia, and gastrointestinal side-effects with diarrhoea being the predominant symptom: this is not reduced with the tablet formulation. The lack of a need for refrigeration is a definite advantage.


Boosted lopinavir has been compared to once- and twice-daily boosted fosamprenavir (the CONTEXT study), unboosted and boosted atazanavir (BMS-043 and BMS-045 studies, respectively), boosted darunavir in treatment experienced but lopinavir-naive patients (the TITAN study) and, in a post hoc analysis, in triple-class treatment-experienced patients failing a PI-based regimen with one or more primary PI mutations (the POWER studies) [9, 20-24]. These are described in detail below. In secondary analyses of further studies, the benefits of including boosted lopinavir in the study drug arm in patients naive to this drug (the TORO study) and the lesser effect of a study drug when boosted lopinavir was included in the comparator arm (the RESIST study) have also been shown [25,26].


Two studies cast doubt over once-daily boosted lopinavir dosing when compared to twice daily in naive patients, both demonstrating significantly higher rates of virological failure in patients with viral loads >100,000 copies/ml. Study ACTG 5073 compared twice daily with once daily and self-administered with directly observed therapy in the once-daily arm [27]. The probability of a sustained virological response of <50 copies/ml was significantly lower when baseline viral load was >100,000 copies/ml. The second study was the ARTEMIS study, which compared once-daily boosted darunavir 800/100mg with once- and twice-daily boosted lopinavir [17]. The primary endpoint of <50 copies/ml at 48 weeks was achieved in 84% of those receiving darunavir compared to 81% of those taking twice-daily lopinavir (NS) and 71% of those taking daily dosing (P<0.05). This is described in more detail below. More recently, a large randomised trial (study M05-730: n=664) compared tolerability of the new tablet formulation to the soft-gel capsule and once versus twice daily did not show any difference at 48 weeks (73.8% had a viral load <50 copies/ml in the twice-daily arm versus 73.2% in the once-daily arm) [28]. Boosted lopinavir has also been used as part of a double protease regimen with both saquinavir and atazanavir respectively and in several monotherapy simplification and naive studies with encouraging results but which are beyond the scope of this article.



Fosamprenavir is a pro-drug of amprenavir. After early indication that boosted amprenavir was a potentially useful component of HAART, a class-comparative study in naive patients (the CLASS study) was undertaken [29]. Patients were randomised in an open-label study to one of efavirenz, ritonavir-boosted amprenavir, or stavudine, with a double nucleoside backbone of lamivudine and abacavir. The primary endpoints were the proportion of patients with viral loads <400 copies/ml at, and the time to virological failure through 96 weeks. At the end of the study, 74% and 68% of patients receiving efavirenz, 66% and 58% of patients receiving boosted amprenavir and 79% and 61% of patients receiving stavudine had achieved viral loads of <400 and <50 copies/ml, respectively. However, throughout the study the efavirenz arm consistently achieved the best results with the longest time to virological failure being demonstrated.


The SOLO study was a randomised open-label non-inferiority controlled trial comparing once-daily boosted fosamprenavir dosed 1400/200mg to twice-daily nelfinavir dosed 1250mg given with abacavir and lamivudine twice daily [30]. The primary endpoint was the proportion of patients with a viral load <400 copies/ml at 48 weeks with secondary endpoints being CD4 cell count rise, tolerability and clinical and laboratory toxicity, viral load <50 copies/ml, and the mean time-averaged change under the curve minus baseline (AAUCMB) in HIV-RNA. Patients were stratified by viral load and were eligible for recruitment if they had a viral load of >1000 copies/ml with no CD4 cell count exclusion. Baseline viral load was 4.8 log10 copies/ml and CD4 cell count approximately 170 cells/mm3. A total of 649 patients received treatment with similar proportions of patients obtaining a viral load <400 copies/ml (69% with boosted fosamprenavir vs. 68% with nelfinavir) and <50 copies/ml (55% vs. 53%). However, in the fosamprenavir arm significantly more patients with viral loads >500,000 copies/ml (73% vs. 53%) and CD4 cell counts of <50 cells/mm3 (73% vs. 68%) achieved viral load suppression at <400 copies/ml, fewer patients developed virological failure (7% vs. 17%), and fewer experienced diarrhoea (9% vs. 16%). At 48 weeks, 210 patients completing the fosamprenavir/r arm of the SOLO study rolled over into an open-label continuation study to examine long-term antiviral response, safety and tolerability [31]. The background regimen was investigator chosen. At week 120, viral loads of <400 copies/ml and <50 copies/ml were maintained in 75% and 66%, respectively with sustained immunological improvement. Data from this has demonstrated that boosted fosamprenavir shows durable responses out to 120 weeks in naive patients with only one case of emergent PI resistance reported to date [32].

The KLEAN study was an open-label non-inferiority trial between soft-gel formulation boosted lopinavir and boosted fosamprenavir, both dosed twice daily with abacavir and lamivudine [18]. Primary endpoints were proportion of patients reaching a viral load of <400 copies/ml by 48 weeks and rates of adverse effects prompting discontinuation. Baseline viral load was 5.1 log10 copies/ml and CD4 count 192 cells/mm3. Eight hundred and eighty-seven patients with viral loads >1000 copies/ml and any CD4 cell count were enrolled randomly 1:1 with stratification by viral load exclusion above or below 100,000 copies/ml. Patients who had a suspected abacavir hypersensitivity reaction were permitted to substitute another NRTI and continue in the study but no other changes were allowed. Findings demonstrated boosted fosamprenavir to be non-inferior to boosted lopinavir (proportions with viral loads <400 copies/ml and <50 copies/ml for boosted fosamprenavir and boosted lopinavir were 73% and 71% and 66% and 65%, respectively). Virological failure was low (3.7% in the fosamprenavir arm vs. 5.4% in the lopinavir arm) and no emergent major protease mutations were identified. Discontinuations because of adverse events were equal between the two arms (12% for fosamprenavir and 10% for lopinavir). There was no difference in all treatment outcomes analysed with non-inferiority demonstrated: the level of dyslipidaemia and gastrointestinal intolerance was also the same. The 96-week data revealed maintenance of virological suppression and continued immunological recovery [33].


CONTEXT was a three-arm study comparing boosted fosamprenavir 700/100mg twice daily, boosted fosamprenavir 1400/200mg daily and boosted lopinavir 400/100mg twice daily in patients who were PI-experienced and failing therapy [20]. The primary objective was to examine the AAUCMB for non-inferiority of the two boosted fosamprenavir arms to boosted lopinavir by intention-to-treat (ITT) analysis and 320 patients were enrolled. At 48 weeks, on primary outcome analysis, both fosamprenavir arms failed to meet the non-inferiority criteria set out in the study design. However, there was no significant difference in the numbers achieving a viral load <50 copies/ml at 48 weeks for the fosamprenavir twice-daily arm (46% vs. 50% for lopinavir) and there were potential confounding imbalances in prior antiviral exposures between the groups that could have disadvantaged fosamprenavir. However, overall fosamprenavir underperformed against lopinavir. Moreover, the availability of more active PIs for patients with prior PI exposure and resistance has superseded the utility of this drug in this context.


Several small studies have evaluated once-daily dosing with 1400mg fosamprenavir and 100mg ritonavir and demonstrated no loss of virological potency or durability and a trend towards improved lipid parameters. The ALERT study randomised 106 patients to either receive daily atazanavir 300mg or daily fosamprenavir 1400mg, both boosted with 100mg of ritonavir and combined with tenofovir and emtricitabine [34]. Both regimens provided similar virological, immunological and fasting total cholesterol, LDL cholesterol and HDL cholesterol, although more patients on fosamprenavir had raised triglycerides and were on lipid-lowering agents. However, in a larger study (the MERIT study), comparing ritonavir-boosted fosamprenavir dosed 700/100mg twice daily with boosted fosamprenavir dosed 1400/100mg once daily, both dosed with fixed-dose lamivudine/abacavir 300/600mg daily, the interim 24-week results did not demonstrate a significant reduction in non-HDL cholesterol and further recruitment was halted despite excellent and equal virological suppression between the arms [35].



Marketed in 2003, atazanavir was the first azapeptide PI. Unboosted atazanavir has been shown to have similar efficacy to nelfinavir and efavirenz in three clinical studies [36-38]. A fourth study (the BATON study), which was a Phase IV single-arm open evaluation of boosted atazanavir with fixed-dose combination tenofovir and emtricitabine, demonstrated excellent viral efficacy (viral load <50 copies/ml in 81% at 48 weeks by ITT analysis) with a favourable metabolic profile [39]. Lastly, a study comparing boosted and unboosted atazanavir with extended release stavudine and lamivudine showed less virological failure and the absence of phenotypic resistance in those taking boosted drug at 96 weeks but with greater rates of hyperbilirubinaemia and increases in lipid levels, reflecting the effect of low-dose ritonavir [40]. Interestingly, DEXA scans demonstrated less emergent lipoatrophy (P<0.05) in those receiving boosted atazanavir with no significant difference in fat accumulation [41]. The main advantages of boosted atazanavir are that the drug is dosed once daily and has fewer adverse effects on lipids than other boosted PI regimens with the possible exception of darunavir. Its main side-effects are hyperbilirubinaemia with or without jaundice, but this is not associated with liver enzyme changes and seldom results in the need to discontinue treatment. A disadvantage is that its bioavailability is highly dependent upon gastric pH, which necessitates its administration with food and a predictable interaction with acid-reducing agents, notably protein-pump inhibitors. This is not overcome by ritonavir boosting, and where alternative antacid strategies cannot be used, atazanavir should be avoided.


Recently, a large (n=883) randomised open-label noninferiority 96-week study has compared boosted atazanavir with boosted soft gel capsule formulated lopinavir (the CASTLE study) [16]. Patients were recruited with a viral load >5000 copies/ml and any CD4 cell count to boosted atazanavir 300/100mg daily or boosted lopinavir 400/100mg twice daily both given with fixed-dose tenofovir/emtricitabine daily and stratified by viral load above or below 100,000 copies/ml as well as geographic region. The primary endpoint was the rate of viral load <50 copies/ml at week 48. Median baseline viral load was 5.0 log10 copies/ml and median CD4 cell count was 205 cells/[mm.sup.3]. Non-inferiority was demonstrated with 78% of those taking atazanavir achieving a viral load <50 copies/ml at 48 weeks compared to 76% of those taking lopinavir, with results being proportionately lower in those with viral loads >100,000 copies/ml. Atazanavir was associated with less dyslipidaemia (P<0.0001 for total cholesterol and triglyceride) and diarrhoea but more icterus (4% vs. 0%) and hyperbilirubinaemia (34% vs. <1% had a bilirubin >2.5 times upper limit of normal) and was generally well tolerated with a low rate of discontinuation (9% for atazanavir and 13% for lopinavir). Virological failures were infrequent (1% with boosted atazanavir and 2% with boosted lopinavir) as were discontinuations for adverse events (2% with boosted atazanavir and 3% for boosted lopinavir). No primary PI emergent mutations were observed.


Atazanavir has also been evaluated in PI-experienced patients failing therapy in two important studies. The BMS-043 study randomised 300 virologically failing patients who had failed at least one PI of whom 25% had at least four major PI mutations and compared unboosted atazanavir and boosted lopinavir with a nucleoside backbone informed by resistance testing [21]. At 48 weeks, boosted lopinavir resulted in significantly greater reductions in viral load and viral undetectability (37% in the atazanavir arm vs. 53% in the boosted lopinavir arm achieved a viral load of <50 copies/ml) although the expected beneficial effect of reduced frequency of dyslipidaemia was demonstrated. The BMS-045 study was a 48-week randomised open-label study of 358 patients who had failed two or more HAART regimens with exposure to all three major antiretroviral classes with a baseline viral load of >1000 copies/ml and CD4 cell count of >50 cells/mm3 [9]. The study compared ritonavir-boosted atazanavir 300/100mg daily, ritonavir-boosted lopinavir 400/100mg twice daily, and atazanavir/saquinavir 400/1200mg once daily, each with tenofovir and another nucleoside. The primary study efficacy endpoint of viral load drop assessed by time-averaged difference and viral undetectability was similar for boosted lopinavir and boosted atazanavir but was inferior for the atazanavir/saquinavir combination (viral load <50 copies/ml at 48 and 96 weeks for boosted lopinavir and boosted atazanavir was 46% and 36% vs. 38% and 33%, respectively: the double PI arm of atazanavir and saquinavir was discontinued at 24 weeks. Further analysis revealed that the more PI resistance present (genotypically and phenotypically) the more likely it was for lopinavir to demonstrate greater efficacy than boosted atazanavir.


Boosted atazanavir has also been used as part of a double protease regimen with both lopinavir and saquinavir, respectively and in PI-switch and monotherapy simplification which are beyond the scope of this article.



Darunavir is a non-peptidic PI that is chemically similar to amprenavir. Dose-defining studies with boosted darunavir were carried out in heavily experienced patients in the POWER 1 and 2 studies. Four dosing strategies were evaluated and a dose of 600/100mg twice daily was chosen.


The ARTEMIS study (an ongoing Phase III open randomised trial) compared once-daily ritonavir-boosted darunavir (800/100mg) with boosted lopinavir dosed either once daily 800/200mg (17%) or twice daily 400/100mg (77%) with tenofovir and emtricitabine in a non-inferiority trial of treatment-naive patients with viral loads >5000 copies/ml and any CD4 cell count [17]. Randomisation was stratified by baseline CD4 cell count and viral load with mean baseline CD4 cell count and viral load being comparable between the arms at 225 cells/mm3 and 4.85log10 copies/ml, respectively. The primary endpoint of <50 copies/ml at 48 weeks was achieved in 84% of those receiving darunavir and 78% of those receiving lopinavir proving non-inferiority. Significantly more patients receiving daily darunavir achieved undetectability than did those receiving once-daily (71%; P<0.05) but not twice-daily lopinavir (81%; NS). In a post hoc analysis stratifying response by initial viral load, any difference was most noticeable in those with a baseline viral load of >100,000 copies/ml when viral undetectability was reached in 79% of those receiving darunavir, 71% of those receiving lopinavir twice daily (NS), and 56% of those on daily administration (P<0.05); however, numbers were small in the once-daily arm and there was no randomisation to the once- and twice-daily arms. Virological failure differed between the three arms (10% with darunavir, 12% with twice-daily lopinavir, and 19% in once-daily lopinavir) although only one isolate from a patient receiving twice-daily lopinavir revealed an emergent primary PI mutation. Boosted darunavir was also associated with significantly less grade 2-4 diarrhoea (4% vs. 8%) and fewer grade 2-4 lipid abnormalities (13% vs. 26% for total cholesterol and 3% vs. 10% for triglyceride levels) when compared to twice-daily boosted lopinavir. Discontinuations for toxicity were lower in the darunavir arm (3% vs. 7%).


A Phase III randomised non-inferiority open-label 96-week controlled trial (the TITAN study) compared boosted darunavir 600/100mg with boosted lopinavir both administered twice daily, in patients who were treatment experienced but lopinavir-naive and were failing therapy with a viral load >1000 copies/ml [22]. The optimised background was chosen by the investigator and informed by resistance test and consisted of two reverse transcriptase inhibitors. Five hundred and ninety-seven patients were randomised and treated of whom 31% were PI-naive. At week 48, superiority of darunavir over lopinavir was demonstrated on ITT analysis at <400 copies/ml (77%for darunavir and 68%for lopinavir) and this difference was replicated at <50 copies/ml (71% vs. 60%). Fewer virological failures in the darunavir arm developed primary PI (21%vs. 36%) and nucleoside (14%vs. 27%) mutations. Discontinuations for adverse events were similar between the arms (6.7% vs. 7.1%) with grade 2-4 diarrhoea less frequent with darunavir (7.7% vs. 14.5%). Darunavir benefits were seen both in patients who had viruses that were fully sensitive (fold change [FC]<10) and in those with reduced susceptibility to lopinavir (FC>10).

The POWER 1 and 2 studies randomised triple-class experienced patients who had failed one or more PI-based combinations and had documented PI resistance with viral loads >1000 copies/ml to one of four darunavir doses (400mg and 800mg once daily and 400mg and 600mg twice daily) or to a comparator PI [23]. Stratification by baseline viral load and use of enfuvirtide was incorporated and tipranavir was excluded as a choice of comparator PI. Overall 131 patients were recruited to the darunavir 600mg twice-daily arm (the chosen dosage to take forward) and 124 to the comparator PI arm. Boosted darunavir outperformed the comparator PI at 48 weeks when evaluated by a drop in viral load by 1 log10 (61% vs. 15%), the proportion achieving a viral load <50 copies/ml (45% vs. 10%), and CD4 cell count increase (102 vs. 19 cells/mm3): these results were maintained out to 96 weeks (39% vs. 9% had a viral load <50 copies/ml). Viral activity could be more accurately defined by the number and type of specific darunavir mutations as opposed to the total number of primary PImutations as defined by IAS. These can be incorporated into a weighted scoring system that can predict overall fold change and virological response to darunavir. Two clinical cut-off values have been derived from the POWER data with a mutation score predicted FC of <10 indicating full susceptibility whereas >40 is resistant. As with theTOROand RESISTstudies, the use of de novo enfuvirtide significantly improved virological results (58% vs. 11% for the comparator arm achieved a viral load <50 copies/ml). Adverse events were mostly lower or similar to those seen in the control PI group. POWER 3 was an open-label nonrandomised Phase III study consisting of combined data from two clinical trials assessing longer-term efficacy and safety [24]. At 96 weeks, 42%of patients had achieved a viral load of <50 copies/ml and the mean increase in CD4 cell count was 103 cells/mm3. Combined safety analysis from all three POWER studies further reinforced the comparative safety and good tolerance of darunavir with most adverse events being of grade 1-2 severity.



Tipranavir is a non-peptidic PI approved in 2005 for use in treatment-experienced patients and which is structurally distinct from the other protease inhibitors.


Tipranavir has been evaluated in a large naive study (BI1182.33) comparing two boosting doses of ritonavir (100mg and 200mg twice daily) with tipranavir 500mg twice daily compared against boosted lopinavir [19]. The study was an open-label, randomised, parallel group, non-inferiority trial. The primary endpoint was the proportion of individuals with a viral load <50 copies/ml at 48 weeks. The nucleoside backbone was tenofovir and lamivudine. Baseline viral load was 5.0 log10 copies/ml and 207 CD4 cells/mm3. Of 562 randomised patients, the rates of <50 copies/ml were 69.2%, 66.7%, and 65.8% in patients receiving boosted lopinavir, boosted tipranavir 500/200mg and boosted tipranavir 500/100mg. Patients receiving boosted tipranavir 200mg twice daily had a significantly increased risk of grade 3-4 hepatotoxicity and hyperlipidaemia. Non-inferiority was shown for the 500/200mg dose but the tipranavir 500/100mg dose was not non-inferior.


The registrational trials for this approval were the two Phase III RESIST studies [26]. These are amongst the largest therapeutic drug trials carried out in HIV. Patients who were triple-class experienced, PI-failing (more than two previous PI-based regimens with more than one PI mutation but fewer than three of the mutations 33, 82, 84 and 90) were randomised to receive either boosted tipranavir 500/200mg twice daily or a comparator PI with an optimised background regimen. In a combined analysis, 1483 patients were recruited of whom 749 received boosted tipranavir dosed 500/200mg twice daily and 737 received an investigator-chosen comparator PI. Primary efficacy outcomes were treatment response (>1 log10 viral load fall) and time to treatment failure. Baseline viral load was 4.73 log10 copies/ml and CD4 cell count 195 cells/mm3. Twice as many patients at week 48 achieved a treatment response (33.6% vs.15.3% obtained a >1 log10 fall in viral load) or a viral load <400 copies/ml (30.4% vs. 14.8%): de novo use of enfuvirtide increased the response in the tipranavir arm to 52%. At week 156, the added value of tipranavir was still apparent with 20.9% maintaining a treatment response compared to 7.5% in the comparator PI arm. Overall, the frequency of adverse events was similar although grade 3-4 elevations in ALT (9.7% vs. 2.1%) and total cholesterol levels (4.2% vs. 0.4%) were more frequently seen in the boosted tipranavir arm at week 48. Using the data set from the RESIST studies, a weighted mutation score has been developed to predict overall fold change and virological response to tipranavir.


The evidence base suggests that there is no longer equipoise as to the decision concerning whether an NNRTI or boosted PI should be used in a naive patient. ACTG 5142 has demonstrated efavirenz has a virological advantage over boosted lopinavir although this is compensated by the genetic frailty of first-generation NNRTIs. Nevertheless, there are frequent circumstances where a boosted PI will remain the first-choice option and in this context, the available data presented here demonstrate that, with the exception of indinavir and tipranavir where the therapeutic window is narrow, all of the PIs are virologically active and virological failure is unlikely to result in primary PI mutations. Hence, the choice is dependent on other factors such as the convenience of the PI (a balance of tablet numbers and requirement for refrigeration/food), tendency to cause dyslipidaemia, and likelihood of drug interactions. With this in mind, the classical disadvantages of PIs are gradually being addressed with the results of ongoing appropriately powered once-daily studies using only 100mg of ritonavir (fosamprenavir and saquinavir in addition to those already described for atazanavir and darunavir) thereby reducing some of the clinical and metabolic adverse effects, the advent of the low-dose ritonavir tablet, which will not require refrigeration, the increased strength of tablets (e.g. atazanavir 300mg) reducing the tablet load further, and the prospect of further co-formulations with ritonavir. Questions remain regarding the importance of sanctuary site penetration (especially the CSF and brain) and the greater likelihood of fat accumulation with PIs, but they are important as an alternative first-line choice for patients in whom an NNRTI is inappropriate and will also be the primary drug used in patients failing their initial NNRTI regimen.


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Correspondence to: Dr Ed Wilkins, Consultant, Department of Infectious Diseases, North Manchester General Hospital, Delaunays Road, Crumpsall, Manchester M8 5RB email:
Table 1: Non-inferiority trials vs. boosted lapinavir
dosed 400/100mg twice daily.

Study name Drug/r Dosing NRTIs n =

KLEAN FOS/r 700/100 bd ABC/3TC 887
CASTLE ATZ/r 300/100 od TDF/FTC 883
ARTEMIS DRV/r 800/100 od TDFFTC 689
GEMINI SQV/r 1000/100 bd TDF/FTC 337
BI1182.33 TPV/r 500/100 bd TDF/3TC 562

Study name Lower bound BL VL <50 vs. d/c vs.
 [log.sub.10] LPV/r LPV/r
 95% CI VL/CD4 copies/ml (%) for AE (%)

KLEAN -12% 5.1/192 66 vs. 65 12 vs. 10
CASTLE -10% 5.0/205 78 vs. 76 2 vs. 3
ARTEMIS -12% 4.9/225 84 vs. 81 3 vs. 7
GEMINI -12% 5.2'138 65 vs. 64 3 vs. 7
BI1182.33 -15% 5.0/207 66 vs. 69 7 vs. 3

bd, twice daily; od, once daily; CI, confidence interval;
AE, adverse effect.

Table 2: Comparison between boosted PIs (adapted from BHIVA
guidelines for the treatment of HIV-1-infected adults with
antiretroviral therapy 2008 and based upon the dose licensed,
or currently pending licensing approval).

 Lopinavir/r ([dagger])

Potency naives [check][check] [check][check]
 [check][check] [check][check]

Durability data [check][check] [check][check]

Convenience [check][check] [check][check]

Tolerability [check][check] [check][check]

Lipid profile [check] [check][check]
([double dagger])

Resistance barrier [check][check] [check][check]
 [check][check] [check][check]

Interaction [check][check] [check][check]

 r ([dagger]) Atazanavir/r

Potency naives [check][check] [check][check]
 [check][check] [check][check]

Durability data [check][check] [check][check]

Convenience [check][check] [check][check]
 [check] [check][check]

Tolerability [check][check] [check][check]

Lipid profile [check] [check][check]
([double dagger]) [check]

Resistance barrier [check][check] [check][check]
 [check][check] [check][check]

Interaction [check][check] [check]

 Darunavir/r Tipranavir/r
 * ([dagger]) * ([dagger])

Potency naives [check][check] [check][check]
 [check][check] [check]

Durability data [check][check] [check]

Convenience [check][check] [check][check]

Tolerability [check][check] [check]

Lipid profile [check][check] --
([double dagger]) [check]

Resistance barrier [check][check] [check][check]
 [check][check] [check]

Interaction [check][check] [check]

[check][check][check][check], excellent; [check][check][check],
very good; [check][check], moderately good; [check], not good;
--, poor.

* Not licensed for treatment of naive patients. ([dagger]) Not
licensed for once-daily treatment. ([double dagger]) Compared
with lopinaivr/
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Title Annotation:LEADING ARTICLE
Author:Wilkins, Ed
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:4EUUK
Date:Mar 1, 2008
Previous Article:Nucleoside analogues in 2008.
Next Article:Key clinical trials of non-nucleoside reverse transcriptase inhibitors in the treatment of chronic HIV-1 infection in adults.

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