HIV Treatment Bulletin

Lipid profile of integrase inhibitor MK-0518: 24 week results compared to efavirenz in treatment naive patients

Simon Collins, HIV i-Base

One of the highlights from last months IAS conference in Toronto was the late-breaker results from the Phase II dose-finding MK-0518 integrase inhibitor vs efavirenz, with tenofovir/FTC. [1]

Similar virological responses were seen in all arms at week 24, but of note, significantly faster suppression, and greater decreases in viral load were seen in all MK-0518 arms at weeks 4-8. As a result of this study, the 400mg BID dose was selected. Ongoing EAP programmes already started in the US, and starting in October in the UK, will collect additional safety data for the fast-track approval application.

Further details from this treatment-naIve study were presented at ICAAC, showing that MK-0518 had a better lipid profile over 24 weeks in treatment naIve patients than efavirenz. [2]

Total cholesterol dropped slightly (by approximately -5mg/dL over the first 12 weeks and was sustained out to week 24, compared to increases of +20 mg/dL in the efavirenz arm.

LDL (bad cholesterol) dropped slightly (by around -5mg/dL over the first 12 weeks sustained out to week 24, compared to increases of +5 mg/dL and +10 mg/dL at 12 and 24 weeks in the efavirenz arm. Differences compared to efavirenz were statistically significant, but were probably too modest to lead to clinical benefit.

HDL (good cholesterol) increased more rapidly in the efavirenz arm (approximetely +6 mg/dL vs +1 mg/dL at 12 weeks) but differences reduced to approximately +4 and +2 respectively at week 24, and were not statistically significant.

Serum triglycerides remained close to baseline for the 100, 200 and 400 mg BD doses of MK-0518 out to week 24 and fell by ~ 50mg/dL in the 600mg BID arm, compared to an increase of approximately +50mg/dL over the first 12 weeks in the efavirenz, arm that were sustained out to week 24.

Table 1: Lipid changes after 24 weeks of MK-0518 or efavirenz

Drug/dose 0518 100mg BD 0518 200mg BD 0518 400mg BD 0518 600mg BD EFV 600mg QD
Baseline Chol mg/dL 168 161 168 162 170
Change Chol (95% CI) -7* (-14 to 0) -2* (-11 to 8) -7* (-15 to 2) -4* (-12 to 5) +19 (+8 to 30)
Baseline TG 129 110 127 155 128
Change Chol (95% CI) +2 (-22 to 26) +5* (-20 to 9) -2* (-23 to 18) -43* (-87 to 1) +43 (-1 to 96)

* p<0.05 compared to EFV

Several interaction studies involving MK-0518 were also presented at ICAAC:

  • Tipranavir/ritonavir slightly lowered Cmin of MK-0518 but didn¬ít affect AUC or Cmax. [3] Tenofovir had no significant interactions with MK-0518. [4]
  • Efavirenz Cmin, AUC and Cmax were all slightly reduced by MK-0518, but no dose adjustment was recommended. [5]

References:

Unless stated otherwise, all references are to the Programme and Abstracts of 46th ICAAC, 27-30 September 2006, San Francisco.

  1. Markowitz M, Nguyen B-Y, Gotuzzo E et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naIve HIV-1 infected patients. XVI International AIDS Conference, Toronto, 2006. Late breaker abstract THLB0214. See HTB September 2006.
    http://www.i-base.info/htb/2805
  2. Teppler H, Azrolan N, Chen J, et al. Differential effect of MK-0518 and efavirenz on serum lipids an lipoproteins in antiretroviral therapy (ART)-naive patients. 46th ICAAC. Abstract H-256a.
  3. Wenning LA, Hanley H, Stone J, et al. Effect of tipranavir + ritonavir on pharmacokinetics of MK-0518. 46th ICAAC. Abstract A-374.
  4. Wenning LA, Friedman E, Kost JT, et al. Lack of a significant drug interaction between MK-0518 and tenofovir disoproxil fumarate. 46th ICAAC. Abstract A-375.
  5. Iwamoto M, Wenning LA, Petry AS, et al. Minimal effect of ritonavir and efavirenz on pharmacokinetics of MK-0518. 46th ICAAC. Abstract A-373.