Boosted PIs: differences emerging in efficacy, tolerability, lipids

Graeme Moyle MD, MBBS, for NATAP


The Abbott M98-863 study is the landmark study for the boosted protease inhibitor era. This randomised study compared in treatment-naive individuals ritonavir boosted lopinavir (LPV, lopiavir/r, Kaletra) with unboosted nelfinavir (NFV, Viracept) on a backbone of d4T (stavudine, Zerit) plus 3TC (lamivudine, Epivir). Participants in the lopinavir/r group experienced a higher level of treatment efficacy relative to the nelfinavir recipients, this outperformance being most evident in the individuals who entered the study with high baseline viral loads and low CD4 counts.

Since the presentation of these data the use of protease inhibitors has shifted over to a preference for using ritonavir-boosting (/r) to reduce tablet volume, increase trough drug exposures, reduce food restrictions and dosing frequency as well as potentially enhance efficacy.

The trade-off for ritonavir-boosting is that there appears to be an increased risk of experiencing dyslipidaemia during therapy. More individuals in the lopinavir/r group of the 863 study experienced grade 3 or 4 hypertriglyceridaemia and hypercholesterolaemia than the nelfinavir recipients. Some studies have also suggested that the background nucleoside therapy may influence the magnitude of lipid changes although further data are required to clarify this point.

Each of the ritonavir boosted protease inhibitor regimens appear to have its sins and virtues. Those that involved relatively more capsules, such as ritonavir with saquinavir or amprenavir, may have the fewest adverse events, the more compact regimens such as the lopinavir/ritonavir co-formulated tablet (Kaletra’) and indinavir/r may have greater problems with dyslipidaemia, gastrointestinal and for indinavir/r, cutaneous and renal problems.

With the array of dosing possibilities including once and twice daily regimens, it is unlikely that comprehensive comparison of the different regimens will be performed. We will therefore need to acquire information about these regimens by comparing their performance in other comparison studies, from clinical cohort studies as well as comparative studies that may not necessarily have adequate statistical power. Additionally, as we begin to understand the relative virtues of each boosted combination reformulations may mean our perspectives about these drugs change. For example, a reformulation of amprenavir as a pro drug (Fos-amprenavir also known as GW 433908) is now in phase III development and promises to reduce the tablet load for amprenavir when combined with ritonavir to 2 + 1 twice daily. A reformulation of saquinavir as a 500mg tablet, also enabling 2+1 dosing with ritonavir twice daily is also entering development.

PIs may be used in a range of circumstances. Some physicians still prescribe these agents in first line therapy, although as ACTG384 suggests that individuals on PI-based (at least nelfinavir-based) regimens have a greater rate of fat loss than those on NNRTI-based (in this study with efavirenz) regimens, this use of PIs first line is likely to decline further.

The main uses are therefore in first line viral rebound and in salvage regimens. In first failure, when clear nucleoside/tide options exist for co-administration just a single boosted PI is likely to be used. In the salvage setting many physicians are using double PI therapy in addition to ritonavir. Studies evaluating both these approaches were reported during ICAAC.

PIs in first line or first failure regimens

The NEAT study is an on-going open-label comparative study of the amprenavir pro-drug (fosamprenavir) dosed unboosted at 1400 mg twice daily compared with nelfinavir 1250 mg dosed twice daily with abacavir + 3TC in 249 individuals with viral loads > 5000 copies/ML at baseline.

Participants were randomised 2:1 to the fosamprenavir:nelfinavir arms. The 24-week results suggested that even unboosted the amprenavir pro-drug was superior to nelfinavir for patients with >100,000 copies at baseline. In individuals commencing therapy with a median baseline viral load of >4.8 log (63,000 copies/ml), the proportion of patients achieving a viral load 100,000 copies, the proportion <50 copies was 42% for fosamprenavir vs 11% for nelfinavir. While for patients with <100,000 copies, the proportion <50 was the same (62%).

While no differences were observed in the proportion of patients responding to < 400 copies/mL in individuals commencing with viral loads 100,000 copies /ml, 71% of fosamprenavir recipients achieved a viral load < 400 copies/ml whereas only 35% of nelfinavir recipients achieved this response. CD4 cell count rose by over 100 cells in each group from the baseline median of 213 cells/mm3. The incidence of dose limiting adverse events and severe laboratory abnormalities in each group was low. However, more patients in the nelfinavir group reported diarrhoea (17%) relative to individuals receiving the fosamprenavir (5%)(p= 0.003).

Studies evaluating fosamprenavir boosted with ritonavir dosed once a day or twice a day are now underway.

The comparative efficacy between ritonavir-boosted indinavir (800/100 mg twice daily) and nelfinavir (1250 mg twice daily) was evaluated in a small study. The Merck protocol 112 is an ongoing study comparing ritonavir boosted indinavir with nelfinavir in combination with two nucleoside analogues of the physicians’ choice in individuals who had previously failed or been intolerant of a NNRTI-based regimen.

The study has included 58 individuals, 30 in the indinavir/ritonavir group and 28 in the nelfinavir group. Most participants had only had a short duration of prior and antiretroviral exposure.

Results at week 12 and week 24 favoured the boosted indinavir group. At week 24 the mean changing viral load with boosted indinavir was 1.4 log and with nelfinavir 0.89 log, with a higher proportion of individuals in the indinavir group achieving undetectable viral load responses as assessed by both the 400 and 400 c/ml (25%) or 200 copies/ml if 50,000 at Week 4 and / or >5,000 at Week 12 and / or > 200 at Week 24 if viral load detectable at baseline) occurred in 59 (19%) patients, 32 (20%) in the IDV/r and 27 (18%) in the SQVs/r arm; this result includes patients who switched from randomised treatment; 122 (40%) of patients discontinued their original treatment.

Switches from the randomised treatment occurred in 66/158 (42%) in the IDV/r and 42/148 (28%) in the SQVs/r arm, switching mainly being due to adverse events. On treatment analysis showed 90% of IDV/r and 93% of SQV/r randomised patients were <400cps/ml at week 48. In the intention-to-treat (ITT, missing or switch = failure) analysis 53% of IDV/r vs. 68% of SQV/r achieved or remained <400cps/ml (p=0.014). Total cholesterol and LDL cholesterol rose only modestly (less than 10%) in individuals who received saquinavir but increased 15 to 20% in those who received indinavir. These differences were statistically significant. Triglyceride increases were also significantly smaller in the saquinavir treated group.

Adverse events in all categories were less common with SQVs/r, the most common adverse events being gastrointestinal. Renal events, such as nephrolithiasis, flank pain and hematuria, were exclusively seen with IDV/r.

Once daily PI use

The Focus study is the first comparative study of a boosted protease inhibitor given once daily with a standard of care efavirenz based triple therapy regimen. The nucleoside analogue choice in the study is by physician choice. The main difference between the regimens is therefore in tablet load, individuals randomised to the once daily saquinavir arm received eight saquinavir tablets (1600 mg) plus one ritonavir 100mg pill with it, whereas individuals and efavirenz arm received 3 efavirenz tablets (600 mg) at night. The saquinavir in this study is dosed as Fortovase, the saquinavir formulation which may have more gastrointestinal toxicity than the hard gel Invirase formulation. The pharmacokinetics and exposure of these two saquinavir formulations when co-dosed with ritonavir are not different. This study included 161 evaluable patients, 81 randomised to saquinavir and 80 to efavirenz. The baseline characteristics did not differ significantly with the viral load being 4.77 log in the saquinavir group and 4.74 log (54,000 copies) in the efavirenz group. Over a quarter of the patients in each group were female and the minority of patients Caucasian.

At 48 weeks follow-up virological outcomes favoured the efavirenz group. By intention to treat it missing = failure analysis 51% of saquinavir and 71% of efavirenz treated patients had viral load less than 50 copies/ml. In the as treated analysis the proportions of patients with viral load is less than 50 copies/ml was 73% for saquinavir and 93% for efavirenz.

Adverse events were also an area of difference between the two treatment approaches. In the saquinavir group more individuals experienced upper gastrointestinal problems, nausea occurring in 22 percent of saquinavir and just 4% of efavirenz treated patients. Diarrhoea rates were similar across the two groups whereas skin problems were less common with saquinavir (1%) and efavirenz (6%) as was dizziness (1% with saquinavir 5% with efavirenz). Overall adverse events were responsible for discontinuation in 12 of 81 saquinavir patients and five of 80 efavirenz patients. Limited differences were observed in laboratory abnormalities with changes in lipids being remarkably similar across the two treatment groups although trends were observed towards more individuals in efavirenz group experiencing grade 3-4 elevations in cholesterol (4% with saquinavir, 8% with efavirenz) and triglycerides (1% with saquinavir 7% with efavirenz). Disturbances in liver transaminases were uncommon, occurring in 4% of saquinavir treated patients and 1% of efavirenz treated patients.

Overall this study suggests that while saquinavir may not be as potent or as well-tolerated as efavirenz it does represent a potential component of a once a day regimen; the main drawbacks to saquinavir are upper gastrointestinal side-effects and the large tablet volume. Both of these matters are currently being addressed. Gastrointestinal side-effects are, anecdotally, less common with the Invirase formulation and a 500mg saquinavir tablet is beginning pharmacokinetics evaluations.

PK issues for double boosted PI

Studies such as ACTG 398 and SPICE have suggested that having two protease inhibitors present at active exposures may lead to better effectiveness. In the era of routine ritonavir boosting of protease inhibitors, many physicians are considering using two active protease inhibitors plus a ritonavir boost in individuals who have been exposed to multiple protease inhibitors or have evidence of significant protease inhibitor resistance. It has been previously demonstrated that an interaction between lopinavir and amprenavir exists when these drugs are combined in the presence of ritonavir: the amprenavir gets a modest boost but lopinavir levels are lower than when the drug is dosed in the absence of amprenavir. Information presented at the 42nd ICAAC Meeting confirmed results from healthy volunteers studies. In individuals with HIV infection adding amprenavir 750 mg twice daily into a Kaletra based combination resulted in lopinavir exposures which were 50% lower than those observed in individuals receiving Kaletra alone. Levels of ritonavir were also modestly reduced. Levels of amprenavir at trough were approximately sixfold higher than those observed in individuals who received amprenavir 1200 mg twice daily alone. These data would suggest that this combination may be best avoided when other second PI options exist to combine with Kaletra. If Kaletra/amprenavir is to be used, consideration should be given to using at least four Kaletra tablets twice daily and therapeutic drug monitoring of both lopinavir and amprenavir levels used to optimise exposure of both drugs.

Studies investigating the potential for other interactions with Kaletra (lopinavir/ritonavir combination tablets) and in the indinavir or saquinavir were reported. The studies included HIV negative healthy volunteers who were initially given saquinavir soft gel 1200 mg TID with food or indinavir 800 mg TID fasted for five days and then included Kaletra three capsules twice daily with the saquinavir changed to 800 mg twice daily and indinavir to 600 mg twice daily for days six to 15. A subset of individuals were also evaluated using 1200 mg saquinavir twice daily with Kaletra. Drug levels for the protease inhibitors involved were drawn when steady state drug levels were established, in other words, on the last day of each dosing period. The doses chosen in this study for indinavir and saquinavir were lower than those currently routinely used when boosted with ritonavir. Combining indinavir with Kaletra resulted in indinavir peak levels that were lower than TID indinavir dosing and trough values which were higher. For saquinavir, peak and trough values were higher when Kaletra was co-dosed and with the standard dosing of saquinavir soft gel. The effects described are similar to those observed when only ritonavir 100 mg twice daily is used as the boosting agent. Neither indinavir nor saquinavir affected the levels of lopinavir.

Double boosted PI therapy in clinical practice

Two studies looked at the use of double boosted protease inhibitors in multiple P I treated patients. The French Puzzle-1 study was really a dose-finding study aimed at evaluating whether additional ritonavir is required when Kaletra is combined with amprenavir. This study included 37 individuals who were previously protease inhibitor experienced but had not received Kaletra or amprenavir. On average the participants had received 53 months of prior protease inhibitors and had seven known protease inhibitor resistance mutations. The patients were randomised to receive new nucleoside analogues (based on resistance testing) together with either Kaletra 3 capsules twice daily with amprenavir 600mg twice daily or these doses with an additional 100 mg of ritonavir twice daily. Thus the standard dosed group received a total of 200 mg of ritonavir per day (100mg twice daily) and the additional boost group received 400 mg of ritonavir per day (200mg twice daily).

Responses to week 26 were reported. The 19 individuals with the additional ritonavir experienced a viral load reduction of 2.5 log compared with the standard dosed group where the main reduction in viral load in 18 individuals was 1.4 log. The additional ritonavir boost resulted in 61% of these individuals achieving a viral load < 50 copies/ml compared with 32% of individuals in those who received the standard dosing. CD4 responses also favoured the additional boost. The rate of adverse events and discontinuation is less similar between the two groups. Despite the added complexity of taking additional ritonavir the study suggests that if the Kaletra/amprenavir combination is to be used in heavily pretreated individuals then the addition of extra ritonavir appears worthwhile.

Details of study: Kaletra + amprenavir and boosted ritonavir in PI experienced patients

A second cohort study evaluated the use of Kaletra with additional saquinavir, a nucloside sparing regimen. Patients entered this study due to toxicity or resistance to nucleosides. Most individuals also had resistance to protease inhibitors in prior treatment regimens. In this case standard boosted doses of each drug were used, three capsules of Kaletra twice daily with 1000 milligrams of saquinavir twice daily. The data presented include 42 of 64 individuals who had received therapy for at least 24 weeks or who have discontinued. The study included individuals with a median CD4 count of 156 cells/mm3 and a viral load of 5.2 log, with a median number of three protease inhibitors used in the past. 26% of patients in the cohort had previously received Kaletra and 48 percent had previously received saquinavir.

Pharmacokinetic evaluations indicated that exposures of saquinavir using this regimen were similar to those reported in historical controls of saquinavir 1000mg combined with ritonavir 100 mg twice daily. The median decrease in viral load from the start of the regimen was 3.5 log with the median viral load at 24 weeks being 60 copies/ml. Nine individuals (21%) discontinued therapy, five from virological failure, three for adverse events and one for a mixture of both virological failure and toxicity. Individuals who did not respond to therapy as assessed by the investigators mainly consisted of individuals who had eight or more protease mutations at baseline and lower CD4 counts.


Protease inhibitors continue to be a key component of antiretroviral regimens although their application is increasingly in individuals who have experienced resistance or intolerance to an initial NNRTI regimen. It is now evident from several studies that ritonavir-boosting of currently approved protease inhibitors results in improved efficacy relative to unboosted approved protease inhibitors.

Differences in boosted protease inhibitors are emerging, the MaxCmin study indicating that boosted saquinavir is similarly effective but better tolerated and less likely to cause lipid disturbance relative to boosted indinavir. An ongoing study is evaluating boosted saquinavir relative to Kaletra across a range of treatment populations.

In individuals who are prior protease inhibitor experienced, many physicians are now considering the use of two PIs boosted with ritonavir. Pharmacokinetic studies suggest that the combination of Kaletra with amprenavir requires careful drug monitoring and dosage adjustment and may require the inclusion of either additional Kaletra capsules or additional ritonavir. Interactions of Kaletra with saquinavir or indinavir had not been observed and evidence of efficacy in a cohort setting has been demonstrated with the combination of Kaletra and saquinavir.

Previous conferences have reported that newer protease inhibitors may also be applicable in these circumstances. For example, atazanavir combined with saquinavir may be as effective as at 400mg twice daily of both ritonavir and saquinavir. Clearly, the choice of combination in the setting will be to a large part influenced by the prior treatment history of these individuals and the result of genotype and phenotype evaluations and therefore studies are unlikely to achieve firm recommendations.


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