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Protease Inhibitor (PI) Experienced patients: therapeutic approaches, ritonavir-boosted regimens
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Reported for NATAP by Dr Graeme Moyle, Chelsea and Westminster hospital, London, UK
Editing by Jules Levin, NATAP
The treatment of individuals to have previously experienced virological failure on a protease inhibitor containing regimen is improving. Boosting the trough exposure of a protease inhibitor, most commonly through the addition of the CYP inhibiting protease inhibitor ritonavir (referred to in this article as /r), can lead to the re-establishing of potent antiretroviral efficacy despite the presence of viral resistance mutations which have led to a shift in virus susceptibility to that drug. Additionally, several new drugs such as Tipranavir and TMC 114 have been specifically designed to retain activity in the presence of mutations which normally lead to resistance to currently approved protease inhibitors. Until these drugs are routinely available many positions are considering the use of two protease inhibitors together with the boosting those of ritonavir as a means of overcoming established viral resistance to members of the protease inhibitor classes. This report will focus on the treatment of individuals for previously received protease inhibitors and on some new data evaluating drug interactions when two protease inhibitors are combined with ritonavir.
TOPICS
BMS 045: Reyataz/r, Kaletra, and Reyataz/SQV
CPCRA 057: single vs boosted PI regimen following single PI failure
Lopinavir/FosAmprenavir/r
TMC 114: new ritonavir boosted PI for patients with PI resistance
Pharmacokinetic studies
--Atazanavir/saquinavir/r: 2 protease inhibitors boosted by ritonavir for patients with PI & HIV drug resistance
--Saquinavir/FosAmprenavir/r: 2 protease inhibitors boosted by ritonavir for patients with PI & Hiv drug resistance
-- Lopinavir/FosAmprenavir/r: 2 protease inhibitors boosted by ritonavir for patients with resistance. Lopinavir with a boost by 100 mg of ritonavir is what makes up Kaletra
Clinical Trials
BMS 045
This study is a randomised open-label comparative study of individuals who have received at least two antiretroviral regimens and who have failed both at least one protease inhibitor and at least one NNRTI. The patients are randomised to receive either atazanavir/r (300 mg/100 mg QD) (n = 120), lopinavir/r (400 mg/100 mg BD) (n = 123) or atazanavir/saquinavir (400 mg/1200 mg QD) (n = 115) in a 1:1:1 ratio. Pharmacokinetic assessment performed separately to the study has shown that the dose of saquinavir chosen in this study does not result in trough plasma concentrations of saquinavir which are sufficient for activity in even PI naive individuals. Details of a more appropriate combination dose for saquinavir and atazanavir are provided later in this report. For the first two weeks after randomisation participants maintained the NRTIs they were receiving at study entry. At week 2, all patients switch their backbone NRTIs and received tenofovir, as a new NRTI, plus an additional NRTI chosen from the results of resistance testing. Of note, there is also a known drug interaction between atazanavir/r and tenofovir that result in levels of atazanavir at trough being approximately 25 percent lower in the presence of tenofovir than in the absence of this a drug. Patients were well matched across the study groups with median baseline viral load of 4.42 - 4.47 log and median baseline CD4 count of 283 -317 cells/cu mm. The primary endpoint for the study was the meaningfull change in log viral load from baseline. And 48 weeks the viral load reduction in the atazanavir/r group was -1.93 log and for the lopinavir/r- 1.87 log (difference 0.13 log copies/ml, 97.5% CI -0.12, 0.39). The atazanavir/saquinavir group significantly underperformed the two ritonavir boosted regimens, achieving a mean reduction of -1.55 log copies/ml. Regarding proportion of patients who achieved an undetectable (< 50 copies/ml) viral load, by intention to treat analysis 38 percent of atazanavir/r, 46 percent of lopinavir/r and 26 percent of atazanavir/saquinavir patients achieved this goal by weak 48. The difference estimate for the time to loss of virological response analysis (TLOVR, the new FDA standard analysis) for atazanavir vs lopinavir was -8% (95% CI -20.4, 4.4) indicating that significant differences were not observed between these two approaches. CD4 cell counts rose by 110 cells/cu mm in the atazanavir/r and 121 cells/cu mm in the lopinavir/r with a response of just 72 cells/cu mm in the atazanavir/saquinavir group.
Atazanavir/r and lopinavir/r are clearly differentiated by their adverse event profile. Similar numbers of individuals in each arm experienced grade 2 or more adverse events. In the lopinavir/r group grade 2 or worst diarrhoea was reported in 11 percent of individuals whereas only 3 percent of individuals in the atazanavir/r group experienced this adverse event. Atazanavir is known to reversibly increase indirect bilirubin. Six percent of individuals in the atazanavir arm were reported to have grade 2 or more jaundice with three percent experiencing scleral icterus whereas events related to bilirubin elevation were not reported in the lopinavir/r group. Withdrawal due to adverse events occurred in 5% of the atazanavir/r and 4% of the lopinavir/r patients. Regarding laboratory abnormalities a grade three or higher bilirubin was reported in 49 percent of the atazanavir/r recipients and less than 1 percent of individuals on the lopinavir/r arm. Differences in hepatic transaminases were not observed. Lipid data favoured atazanavir/r. Total cholesterol, LDL cholesterol and triglycerides declined in the atazanavir/r group whereas these parameters rose in the lopinavir/r group with differences in total cholesterol and triglycerides being statistically significant. Patients in the atazanavir group were significantly less likely to receive lipid-lowering therapy during the course of the study; only 8% of atazanavir patients receive lipid-lowering therapy compare with 19% of those on the lopinavir/r arm. Similarly, the rate of anti diarrhoea use were also lower in the atazanavir/r arm (6%) compared with the lopinavir/r arm (24%).
CPCRA 057
This study, while some updated in its design and entry criteria, provides valuable insight into the best way to treat after initial PI failure. The study randomised individuals who would failed either nelfinavir (n = 38) or, indinavir or indinavir (n=30) to receive a regimen including new NRTIs, their first NNRTI and either one or two protease inhibitors. The prescribed 2 PI combinations included RTV/SQV (400mg/800mg, 80%), RTV/IDV (400mg/400mg, 9%), SQV/NFV (1000mg/1250mg, 3%). The prescribing NNRTIs was efavrienz (88%) or nevirapine (12%). Single PI were IDV (68%)or amprenavir (21%), in the NFV group, and NFV (93%) or APV (7%) in the I/R group.
Patients included in the study had a medium baseline CD 4 count of 255 to 267 cells/cu mm and a baseline viral load of 4.1-4.2 log copies/ml. Whilst the time to first follow-up viral load greater than 10,000 copies/ml or death (the primary study endpoint) did not differ between groups, result of CD 4 and viral load analyses favoured the use of two protease inhibitors. These data are consistent with previous double PI studies such as SPICE and ACTG398. The proportion of individuals with a viral load less than 400 copies/ml 12 months after randomisation was 36 percent of individuals who received a single PI and 61 percent of individuals who received two protease inhibitors (p = 0.08). The log reduction in viral load at months 12 was -0.59 in the single PI group and -1.41 in the double PI group (p = 0.05). Regarding CD4 cell count, the single PI group experienced a decline in CD 4 count of 11 cells/cu mm whereas the double PI group experienced a rise of 69 cells/cu mm (p=0.04). This study supports the idea that individuals who experience virological rebound on their first protease inhibitor should include two active protease inhibitors in the next regimen. The study authors summarized the pharmacological boosting of the second PI with RTV appears to have improved responses compared to the single PI regimen; as well, RTV may also have acted as another potent drug in the2 PI regimen since it was used at a dose of 400 mg twice daily. Suboptimal response in the1 PI treatment group may be dueto lack of pharmacologic boosting or to preexisting resistance.
TMC 114: new PI
Tibotec have both and NNRTI and PI in clinical development. Those agents appear active against the majority of viruses selected for by the approved agents within these drug classes. The Tibotec PI, TMC114 was investigated in a dose ranging study over 14 days in individuals currently failing in approved protease inhibitor. The approved protease inhibitor was replaced in the regimen by one of three doses of TMC 114, TMC114/RTV at doses of 300/100 mg twice daily (n = 13), 600/100 mg twice daily (n = 12) or 900/100 mg daily (n = 13), with a control group of individuals who did not switch off their PI. Baseline genotypic and phenotypic testing were performed to investigate the determinants of TMC 114 activity. The median baseline viral load was 4.3 log10 copies/mL and the median CD4 cell count 305 cells/mm3. Median changes in viral load were 1.2, -1.3, and -1.5 in the 300/100 twice daily, 900/100 daily, and 600/100 twice daily group, respectively. There was no statistical difference in antiviral activity between the 3 arms. All TMC114/RTVgroups were statistically-superior to the control group (p <0.001). A univariate analysis indicated that genotypic, phenotypic, pharmacokinetic and IQ parameters were not predictive for change in viral load at day 14. These data indicate that this is a highly active protease inhibitor which is likely to advance into further development and be useful in individuals with virus resistant to currently approved protease inhibitors.
Pharmacokinetic studies
Atazanavir/saquinavir/r
A pharmacokinetic study in 18 HIV positive patients investigated the co-administration of saquinavir/ritonavir 1600/100 and atazanavir 300 mg once daily. The study demonstrates that the addition of atazanavir to the regimen substantially increased saquinavir exposure, producing statistically significant increases in saquinavir Ctrough, Cmax and and 24 hour AUC. The addition of atazanavir to the once daily saquinavir/ritonavir regimen also influenced the pharmacokinetics of ritonavir. Ritonavir Cmax and AUC0-24h increased slightly and the Ctrough decreased. Atazanavir exposures observed were consistent with historical control data for the atazanvir/ritonavir 300/100mg once daily dose, indicating that saquinavir does not affect atazanavir pharmacokinetics. The mechanism by which saquinavir exposure was increased during atazanavir co-administration is unclear. The increased ritonavir concentrations may result in a greater inhibition of CYP450 3A4, which is responsible for saquinavir metabolism and clearance. However, previous studies have indicated that only small and non-significant increases in saquinavir exposure follow the administration of dosages of ritonavir higher than 100 mg. Effects on CYP450 isoforms, other than 3A4 are also unlikely to explain this pharmacokinetic event, since it has not been shown that isoenzymes different that 3A4 are responsible for saquinavir metabolism. When saquinavir/ritonavir/atazanavir are co-administered drug efflux mediated by P-gp and other transmenbrane transporters may be further inhibited at the level of the intestinal epithelium. Therefore, drug absorption may be enhanced by this combination. Further studies are warranted to investigate the relationship between atazanavir and P-gp function in vivo.
Although saquinavir/ritonavir/atazanavir was well tolerated by the patients enrolled in the study, reversible indirect hyperbilirubinemia was common after the addition of atazanavir to the regimen. This drug combination presents a possible therapy for PI and treatment experienced patients with extensive drug resistance.
Saquinavir/FosAmprenavir/r
Two formulations of amprenavir exist, a soft gel amprenavir formulation, and a hardened tablet containing the amprenavir pro-drug fosamprenavir. Fosamprenavir is rapidly hydrolysed to amprenavir by cellular phosphatases in the gut epithelium during drug absorption. Amprenavir not only undergoes CYP450 metabolism but also inhibits and induces some CYP isoforms. The combination of saquinavir/amprenavir has been previously found to reduce saquinavir exposure by approximately 20%, even in presence of ritonavir, compared with historical data for saquinavir when administered without amprenavir. The drug interaction between fosamprenavir and saquinavir was investigated in 18 HIV positive patients stable on saquinavir/ritonavir 1000/100 mg twice daily; in addition, the use of 200mg RTV twice daily was investigated.
The co-administration of fosamprenavir twice daily with saquinavir/ritonavir 1000/100 mg twice daily resulted in a non-statistically significant decrease in saquinavir pharmacokinetic parameters (by 14%, 24% and 9% for saquinavir AUC0-12h, Ctrough and Cmax). This decrease could be compensated for by the addition of further 100 mg ritonavir twice daily. This resulted in an increase of saquinavir pharmacokinetic values compared to baseline (by 12%, 3% and 20% for AUC0-12h, Ctrough and Cmax, respectively). Ritonavir pharmacokinetic parameters were also significantly decreased after the addition of fosamprenavir to the regimen prior to the dose increase in ritonavir. Amprenavir AUC0-12h, Cmax, and Cmin values were 27%, 29%, and 40% lower compared with previously reported data for fosamprenavir/ritonavir 700/100 mg twice daily. It is not clear if this represents inter study variation or an unexpected effect of saquinavir on fosamprenavir pharmacokinetics. However, when fosamprenavir was combined with both 100 and 200 mg ritonavir, 17/18 patients maintained Ctrough levels above the amprenavir therapeutic threshold recommended for treatment-naive patients (400 ng/mL) and 10/18 were above the threshold identified for treatment-experienced patients (1200 ng/mL).These data suggest that the optimal dose combination for the three agents is saquinavir/ritonavir/fosamprenavir 1000/200/700 mg twice daily. This regimen also presents a possible therapy for PI and drug resistant patients with extensive resistance.
Lopinavir/FosAmprenavir/r
A complex, unfavourable interaction is observed when amprenavir or fosamprenavir is combined with lopinavir/ritonavir. Evidence, from both HIV-infected patients and healthy volunteers, suggests that in addition to decreased lopinavir/ritonavir following induction of CYP450 by amprenavir, lopinavir also seem to cause a decrease in amprenavir, albeit to a lesser extent.
The pharmacokinetics of the combination of fosamprenavir and lopinavir/ritonavir has been previously investigated in 33 ARV experienced patients at steady-state. The study showed a significant decrease in both amprenavir and lopinavir AUC and Ctrough. An approximate 70 and 50% decrease in amprenavir and lopinavir plasma exposure was observed. A prospective, non-blinded, randomized, 3 treatment, 3-way crossover study in seronegative subjects was reported investigating the separation of lopinavir/r and fosamprenavir dosing by 4 or 12 hours and inclusion of additional ritonavir. To ensure maximal CYP450 induction, subjects were given 908+LPV/RTV 700 mg+400/100 mg twice daily simultaneously for 10 days, then randomized to receive 3 treatments (7 days each) followed by pharmacokinetic sampling: 908+LPV/RTV 700 mg+400/100 mg twice daily simultaneously (0HR); 908/RTV 700 mg/100 mg twice daily + LPV/RTV 400/100 mg twice daily, separated by 4 hours (4HR); 908/RTV 1400/200 QAM+LPV/RTV 800/200 QPM (12HR). The data indicated that dose separation corrected LPV exposure (although increased RTV doses may have contributed) but did not correct adequately be fosamprenavir exposures. Further investigation is needed to determine an optimal dosing strategy when combining fosamprenavir and LPV/RTV and us for the time being this combination should be avoided unless therapeutic drug monitoring is available.
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