After 48 weeks of study, and 24 weeks in the real world, darunavir continues to show staying power

POWER 1, 2 & 3

Some 24- and 48-week results from all three POWER studies – sponsored by Tibotec, who developed and marketed darunavir – have previously been reported, but these new reports include more detailed results, in particular adverse event data.

Briefly, POWER 1 and 2 were randomised, controlled ‘salvage’ studies where 131 highly treatment-experienced participants were randomised to darunavir/ritonavir 600/100mg twice-daily and another 124 highly treatment-experienced participants received any other approved ritonavir-boosted PI along with an optimised background regimen – which included two or more NRTIs and/or enfuvirtide (T-20, Fuzeon).

POWER 3 was itself a combination of two open-label, non-randomised, rollover studies comprising a total of 324 highly treatment-experienced participants who received darunavir/ritonavir 600/100mg twice daily along with an optimised background regimen

The recently-approved ‘salvage’ protease inhibitor (PI), darunavir (Prezista), boosted by a small additional dose of ritonavir (Norvir) and in combination with an optimal background regimen, continues to show itself to be safe and potent, according to three studies presented last week to the Frontiers in Drug Development for Antiretroviral Therapies (DART) conference in Cancun, Mexico. At 48 weeks, a total of 45% of over 450 POWER 1, 2, and 3 participants had a plasma viral load below 50 copies/ml, with short- and longer-term side-effects and toxicities comparable to most first-line boosted PIs.

Virological results

At week 48, 45% of the pooled POWER 1,2 and 3 participants had viral loads below 50 copies/ml; and more than 90% who had reached this point at week 24 continued to remain ‘undetectable’ at week 48.

A total of 62% on darunavir/r in POWER 1 and 2 (and 61% in POWER 3) had at least a one log reduction in viral load from baseline at week 48. Furthermore, 73% of POWER 1 and 2 participants on darunavir/r, and 82% of POWER 3 participants, who had achieved a greater than one log drop in viral load at week 24 – but not an ‘undetectable’ viral load – maintained or improved their virologic response by week 48.

Toxicity and side-effects

The most commonly reported adverse events in participants on darunavir/r in all three POWER studies were (mild-to-moderate) diarrhoea, nausea, and headache. A total of 9% of those on darunavir/r in POWER 1 and 2 discontinued due to adverse events compared with 5% on other ritonavir-boosted PIs.

In POWER 3, 25% of participants experienced a grade 3 or 4 laboratory adverse event (although not all of these might have been due to darunavir/r alone). A total of 7% experienced high amylase (a predictor of pancreatitis); another 6% had high triglycerides and/or high blood sugar; 4% had high total cholesterol; and around 3% had unusually high liver function tests.

However only 2% discontinued due to adverse events. Although 14% experienced diarrhoea and 10% experienced nausea in POWER 3, the investigators say that there was "no [darunavir/r] dose relationship...observed and there was no clear relationship between...dose and the frequency or severity of [adverse events]."

Triglyceride levels were above normal for all POWER 1 and 2 participants at baseline. By week 48, mean triglyceride levels were 24% lower in those on darunavir/r and 25% for those on other boosted PIs. Mean LDL, HDL, and total cholesterol levels remained within normal ranges.

Utility of T-20

In participants with one or more darunavir-associated mutations at baseline, T-20 made no apparent contribution to potency (62% vs. 64% with ‘undetectable’ viral loads at week 48 in those who used T-20 for the first time compared with those who didn’t use T-20). However, the participants who didn’t use T-20 appeared to be less treatment-experienced than those who did, since they had a higher mean CD4 cell count and more active NRTIs in their optimised background regimen at baseline (198 vs. 112 cells/mm³, and 41% vs. 22% with two or more active NRTIs, respectively).

T-20 made much more of an impact in those with two or more darunavir-associated mutations at baseline. A total of 62% of participants with two darunavir-associated mutations who used T-20 for the first time achieved an ‘undetectable’ load, compared with 40% who did not use T-20. And 43% of participants with three or more darunavir-associated mutations who used T-20 for the first time achieved an ‘undetectable’ load, compared with 14% who did not use T-20.

Efficacy predictors

Week 48 efficacy was analysed by various phenotypic and genotypic resistance tests.

When examining baseline phenotypic fold change to darunavir/r ‘undetectable’ viral load at week 48 was achieved by 54% of participants with a tenfold or lower change at baseline, compared with 28% and 14% of patients with a ten- to fortyfold change, and a greater than fortyfold change, respectively.

A total of 53% of participants with two or fewer darunavir-associated PI mutations achieved an ‘undetectable’ viral load at week 48, compared with 20% of participants with three or more darunavir-associated PI mutations. Similarly, 54% of participants with two or more active NRTIs in their optimised background regimen achieved an ‘undetectable’ viral load at week 48.

Another Tibotec-sponsored study – examining PI resistance in around 208,000 US samples submitted to testing labs between 1998 and 2006 – found that, on average, around six percent of individuals had three or more darunavir-associated PI mutations, although this increased to closer to 10% in the first six months of 2006. This compares with an approximate 2% prevalence in the UK, reported last month.

Real world experience

A fourth Tibotec-sponsored presentation, from an HIV clinic in Houston, Texas, found that real world results of darunavir/r in the drug’s Expanded Access Programme were similar to – or even better than – those of the pooled POWER studies.

Here, 38 individuals (average age 48, mostly white males, two coinfected with hepatitis C) with limited or no treatment options (on average they’d received eleven prior antiretrovirals); more than 95% had burned through three or more PIs – including tipranavir for one in three – and 39% had previously taken T-20. They received twice-daily darunavir/r 600/100mg along with a variety of other antiretrovirals. Of the 23 who took T-20, fifteen had not taken it before.

By October 2006, all had been on darunavir for at least 12 weeks, and 23 had used the drug for 24 weeks. At baseline, mean viral load and median CD4 cell count were 126,775 copies/mL and 144 cells/mm³, respectively.

Nine adverse events were considered “possibly related to” darunavir: two mild rashes; one mild bout of nausea; two abnormal (grade 2) liver function tests; one high (grade 2) total cholesterol test; one very high (grade 3) triglyceride test; one increased (grade 2) creatinine level; and one increased (grade 2) total bilirubin.

Another two serious events occurred that were considered unrelated to darunavir: one T-20 injection-related haematoma requiring surgery, and one death.

After 12 weeks, 54% achieved a viral load below 50 copies/mL. At week 24, 11 of the 22 for whom data were reported (50%) were ‘undetectable’ – ten had achieved this by week 12. Total mean viral load reduction at week 24 was 2.17 log₁₀ copies/mL and mean CD4 increase was 109 cells/mm³

Of the 22 patients with CD4 data at baseline and at week 24, 42% had CD4 counts below 50 cells/mm3 at baseline. By week 24, 80% had CD4 cell counts above 100 cells/mm3.