Boosted PI therapy antiretrovirals in treatment-experienced patients: SQV/r, ATV, ATV/r

Graeme Moyle for

New data on the use of antiretroviral regimens in individuals who have experienced failure on at least one prior antiretroviral combination mainly focused on comparative data between different protease inhibitor based regimens. The main contenders for this market currently dominated by lopinavir/r (Kaletra) are atazanavir and saquinavir. New data on fosamprenavir, a third option to lopinavir/r now in advanced development, were not presented. In general, the great challenge with organising studies in treatment experienced patients is creating a large enough population to have adequate statistical power and to avoid modest differences in entry characteristics influencing trials outcome.

MaxCmin2: saquinavir/r vs. lopinavir/r

The MaxCmin studies are a series of comparative randomised trials evaluating the efficacy and tolerability of boosted protease inhibitor drugs in mixed patient populations, including approximately equal proportions of individuals commencing protease inhibitors for the first time, individuals responding to protease inhibitor therapy but experiencing tolerability or adherence issues and individuals who have failed a prior PI regimen. [1]

In MaxCmin1, saquinavir 1000mg BID/ritonavir 100mg BID was compared with Indinavir 800mg BID/ritonavir 100mg BID. The intention to treat outcome of the study favoured the saquinavir group, whereas in the as treated analysis virological success was similar. Saquinavir/r demonstrated a clear lipid advantage relative to Indinavir/r.

In MaxCmin2, saquinavir 1000mg BID/ritonavir100mg BID was compared with lopinavir 400mg BID/ritonavir 100mg BID (as Kaletra) in 339 individuals. Baseline characteristics indicated that 48% of patients in each group were PI naive and 32% of individuals were virological failures on a prior PI based regimen. The median baseline CD4 cell count was 240 cells/mm3 and baseline viral load 4.5log (31,000 copies/ml) with 21% of individuals less than 400 copies/ml at baseline. No significant differences between groups were observed at baseline. By intention to treat (exposed) analysis at 48 weeks of follow-up for HIV RNA less than 50 copies/ml, the proportion of patients undetectable was 57% for the saquinavir/r and 65% for the lopinavir/r groups (p= not significant). The on treatment analysis however, favoured saquinavir/r with 75% less than 50 copies/ml compared with 70% on the lopinavir/r arm (p= not significant).

For the endpoint of time to virological failure (ITT/exposed, failure including all discontinuations as well as ‘true’ viral failure) the lopinavir group significantly outperformed the saquinavir group (p=0.009). Differences in the time to virological failure in the on-treatment analysis were not observed. The main driver of differences between the groups was the number of individuals who discontinued from the saquinavir/r group for non-fatal adverse events (20/172 versus 13/167 for the saquinavir and lopinavir groups, respectively) and patient choice/non-compliance (13/172 versus 5/167 for the saquinavir and lopinavir groups, respectively). Overall, 29% of saquinavir and 13% of lopinavir patients discontinued the study (p= 0.001) with 48% of discontinuations being due to non-fatal adverse events. No difference in the risk or time to a grade 3 or 4 adverse event was seen between the arms. No differences between the immunological response was observed between arms.

The interpretation of these results is quite difficult as it would appear the only differences in performance of the drugs is observed when individuals who discontinued for non-fatal adverse events or personal reasons are taken into account. The reasons for these patients discontinuing is likely to lie in two aspects of saquinavir administration. Firstly, the saquinavir arm required individuals to take six capsules twice daily compared with the three capsules twice daily in the lopinavir arm. Additionally, the Fortovase formulation of saquinavir was used in this (and the Maxcmin1) study, this formulation is generally considered to be less well-tolerated than the hard gel Invirase formulation. Reformulation of saquinavir as a hardened tablet taken as two tablets (500mg tablets) twice daily plus one capsule of ritonavir twice daily is currently in advanced development and may well remedy many of the obstacles to saquinavir use.

BMS 043: unboosted atazanavir vs. lopinavir/r

This was a randomised open-label comparative study of atazanavir 400 mg QD versus lopinavir/r 400/100 mg BD in individuals failing a protease inhibitor based regimen. [2]

Two new nucleoside analogues were chosen on the basis of resistance testing. One hundred and fifty patients were randomised into each arm, with 144 people in the atazanavir group and 148 in the lopinavir/r group commencing therapy. Baseline CD4 count was 288/mm3 in the atazanavir group and 261/mm3 in the lopinavir/r group, with the median viral load being 4.18 and 4.14 log, respectively. Baseline resistance testing suggest fewer patients had viruses susceptible to atazanavir (72%) compared with lopinavir/r (86%), although the proportion of patients with >4 protease inhibitor mutations at baseline was similar between groups (26 versus 23%, respectively). Both drugs were well tolerated over 24 weeks of follow-up with just one person in the atazanavir group and four in the lopinavir/r group discontinuing due to adverse events.

At 24 weeks of follow-up the atazanavir group had experienced a mean reduction in viral load of -1.67 log compared with 2.11 log in the lopinavir/r group. Analysis by time average difference estimates indicated a significant advantage for the lopinavir/r group (p=0.0032). As a result of these analyses the study was discontinued. By intention to treat analysis, the proportion of patients achieving less than 400 copies/ml was 59% and 77% for the atazanavir and lopinavir/r groups respectively. Using the 50 copies/ml cut-off, the values were 38 and 54%, respectively.

Factors associated with a virological response to atazanavir (achieving a viral load less than 400 copies/ml at week 24) included a baseline IC 50 <2.5-fold above control, exposure to < 2 protease inhibitors and the absence of any nucleoside analogue mutations in the baseline sample. Indeed, when subjects with no nucleoside analogue mutations at baseline were considered the mean reduction in viral load at 24 weeks in the atazanavir group (n=32) was 1.96 log as compared with 2.06 log in the lopinavir/r group (n=26).

Changes in lipids favoured the atazanavir group with a 2% decline in total cholesterol, a 6% decline in LDL, a 12% increase in HDL and 2% decline in triglycerides as compared with the lopinavir/r group where total cholesterol rose 17%, LDL rose 5%, HDL increased 18% and triglycerides increased 55%.

Of note, these analyses were performed excluding individuals who received or commenced lipid-lowering therapy during the study and thus may be considered conservative analyses. The main adverse effect associated with atazanavir use is elevation of indirect bilirubin. Only 3% of individuals receiving atazanavir reported clinical jaundice although 22% of individuals were noted to have a grade 3/4 bilirubin elevation.

BMS-45 study: boosted atazanavir vs. lopinavir/r

Metabolism of atazanavir is inhibited by administration with ritonavir. Both the maximum concentration and the elimination half-life of atazanavir are affected, leading to substantial increases in atazanavir exposure and trough concentration over the 24-hour dosing interval. Using 300mg of atazanavir with 100mg of ritonavir (ATV/r) leads to an atazanavir exposure that is approximately threefold higher at trough than the exposure observed with 400mg of atazanavir dosed alone.

The BMS 045 study randomised 358 individuals who had failed at least two prior regimens including exposure to all three approved drug classes to receive either ATV/r (n=120), ATV 400mg QD plus saquinavir 1200mg QD or lopinavir/r 400/100mg BD. [3]

During the first two weeks of the study, participants maintained their background nucleoside analogue therapy and switched their failing PI or NNRTI to their randomised new therapy. After two weeks, the background NRTI therapy was switched to include tenofovir plus one new nucleoside analogue based on resistance testing. Baseline demographics for the ATV/r, ATV/SQV 1200mg QD and lopinavir/r 400/100mg BD indicated patients were well matched for viral load (4.44, 4.42 and 4.47 log, respectively) and CD4 cell count (317,286, and 286/mm3, respectively). Duration of prior antiretroviral therapy, number of agents within each class to which individuals have been exposed and baseline susceptibility to atazanavir and lopinavir were similar across groups.

The regimens were generally well-tolerated with 6%, 12% and 5% of ATV/r, ATV/SQV and LPV/r groups respectively discontinuing. Adverse events were the cause of discontinuation in 3, 4, and 2% of individuals in each group, respectively.

The mean change in viral load through week 24 was 1.88, 1.62 and 1.89 for the ATV/r, ATV/SQV and LPV/r groups, respectively. For the ITT: time to loss of virological response (ITT:TLOVR) analysis, using the 400 copies/ml cut-off the proportion of patients undetectable at week 24 was 64, 44 and 62%, respectively. Using the less than 50 copies/ml cut-off the proportion of patients undetectable was 39, 23 and 42%, respectively. Detailed statistical analysis was not provided, however limited data suggested that in no analysis was a difference observed between ATV/r and LPV/r but that both groups consistently outperformed the ATV/SQV arm.

Lipid data favoured the atazanavir regimens. Comparing ATV/r with LPV/r, total cholesterol fell by 8% compared with a rise of 3%, LDL cholesterol fell by 10% compared with a decline of 4% and triglycerides fell by 2% compared with a rise of 31% in the two groups, respectively. In general, the group containing ATV/SQV had a similar impact on lipids as ATV/r.

During the study 7% of individuals randomised to ATV/r, 12% of individuals randomised to ATV/SQV and 15% of individuals randomised to LPV/r commenced lipid lowering therapy. These differences in the requirements for lipid lowering therapy between agents that perform similarly virologically may have important resource implications.

Regarding adverse events, diarrhoea was reported by 3% of ATV/r and 11% of LPV/r recipients whereas jaundice occurred in 6% and scleral icterus in 3% of ATV/r recipients but in no patients in the LPV/r group. Grade three or four bilirubin elevation was reported in 45% ATV/r recipients but <1% of LPV/r recipients.


These three studies presented at the IAS conference provide health care professionals with an opportunity to consider which protease inhibitor regimens are the best choice when a protease inhibitor drug is needed.

In individuals experienced with a protease inhibitor these studies would suggest that un-boosted atazanavir and atazanavir combined with saquinavir may be less good choices than either lopinavir/r, atazanavir/r or saquinavir/r. Atazanavir/r appears to have lipid advantages relative to lopinavir/r.

Additionally, atazanavir/r provides therapy in the form of three pills QD compared with three pills BD with lopinavir/r and six pills BD with saquinavir/r. The downside to atazanavir/r is clearly the frequency of elevation of indirect bilirubin. Data from these studies however, would suggest that this infrequently leads to a diagnosis of jaundice or to atazanavir discontinuation. Ongoing efforts to reformulate saquinavir into a more compact tablet form are likely to address some of the key obstacles to the more widespread use of this agent. The boosted protease inhibitor market is becoming very competitive.


Unless stated otherwise, references are to the programme and abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July 2003, Paris.

  1. Youle M, Gerstoft J, Fox Z et al. The final Week 48 analysis of a phase IV, randomised, open-label, multi-centre trial to evaluate safety and efficacy of lopinavir/ritonavir (400/100 mg bid) versus saquinavir/ritonavir (1000mg/100mg bid). Abstract LB23.
  2. Nieto-Cisneros L, Zala C, Fessel WJ et al. Antiviral efficacy, metabolic changes and safety of atazanavir (ARV) versus lopinavir/ritonavir (LPV/RTV) in combination with 2 NRTIs in patients who have experienced virologic failure with prior PI-containing regimen(s): 24-week results from BMS AI424-043.Abstract 117.
  3. Badaro R, DeJesus E, Lazzarin A et al. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI in patients who have experienced virologic failure to multiple HAART regimens: 16-week results from BMS AI424-045. Abstract 118.


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