Integrase inhibitor MK-0518: early results show greater early potency than efavirenz

Simon Collins, HIV i-Base

The most exciting data at this meeting probably related to the late breaker from Merck, that presented limited 24-week data from a phase-II study of their integrase inhibitor MK-0518 in treatment-naive patients. [1]

Marty Markowitz from the Aaron Diamond Insitute presented results from a two-part, five arm, 48-week, dose-finding study. For the first ten days, 40 patients were randomised to receive MK-0518 monotherapy dosed at 100, 200, 400, or 600 mg or a placebo, twice daily. After an interim analysis (reported at CROI this year [2]), 150 new patients were randomised to either one of the MK-0518 doses plus tenofovir/FTC, or the comparitor arm of efavirenz/TFV/3TC. Patients from part one continued the same dose of MK0518 in part two, adding TDF/FTC.

Mean baseline CD4 and viral load were 270-330 cells/mm3 and 4.6-4.8 log copies/mL respectively, with 29-43% diagnosed with AIDS, across the groups. Approximately 80% were male, and 70-90% were Caucasian. Baseline characteristics are detailed in Table 1.

Table 1: Baseline characteristics in MK-0518 phase II study

100mg 200mg 400mg 600mg placebo
n 39 40 41 40 38
% male 85 73 90 73 76
% Caucasian 18 35 34 35 32
Mean CD4 314 296 338 271 280
HIV RNA log 4.8 4.8 4.6 4.8 4.8
% with AIDS 31 33 29 43 37

Although the printed abstract included limited 16-week data, the oral presentation reported here included 24-week data on 202 patients.

In summary, all groups showed a -2.0 log drop in viral load by week 2, that was sustained out to week 24. Suppression to <50 copies/mL at week 24 was achieved by 90-95% of patients receiving higher doses of MK-0518 compared to 92% of patients receiving efavirenz and 87% of the low dose MK-0518. These differences were not statistically significant.

However, when looking at early response at weeks 4 and 8, a statistically significant difference in the percentage of patients reaching <50 copies/mL was seen in all MK-0518 groups compared to the efavirenz arm (p<0.001). The approximate differences were 60-70% vs 20% at week 4 and 70-80% vs 40% at week 8. The clinical implications are unclear, but this early higher potency compared to the current best standard of care, generated much of the excitement over this drug.

CD4 increases were similar in all arms: approximately +50-100 cells/mm3 at week 2, increasing to +100-150 cells/mm3 in all groups by week 24. Discontinuations and side effects were low in all groups and are summarised in Tables 2 and 3 respectively.

Table 2: Discontinuations over 24 weeks

Mk-0518 placebo/EFV
100mg 200mg 400mg 600mg
n enrolled 41 40 41 40 41
n treated 39 40 41 40 38
Discontinued by wk 24 0 5 1 2 2
Efficacy 0 2 0 0 0
Side effects 0 0 0 1 0
Other 0 3 1 1 2

Table 3: Side effects reports >5% patients

MK-0518 (all doses) EFV
Nausea 11 13
Headache 9 24
Dissyness 8 26
Insomnia 7 11
Abnormal dreams 6 18
Flatulence 6

Additional side effects seen at >5% in the efavirenz group included nightmares (11%), vomiting (8%), malaise (8%), fatigue (5%), disturbance in attention (5%), lethargy (5%), anxiety (5%)

Most clinical side effects were mild to moderate. There were 8 serious adverse events overall (7/160, 4% in the 4 MK-0518 groups, 1/38, 3% in EFV group); none were considered drug related. There was one discontinuation for increased AST/ALT. Grade 3 / 4 laboratory abnormalities were uncommon.


Integrase is one of three virally encoded enzymes that is essential for HIV replication. While reverse transcriptase and protease have proved effective targets for drug development, despite many years of research, largely led by Merck, compounds that target integrase, have only recently shown efficacy in vivo. It is very exciting to see this data.

Integrase regulates a two-step process including initial chain termination followed by strand transfer where RT-transcribed viral DNA becomes integrated into host cell DNA. MK-0518 is active at the second of these stages.

While MK-0518 will still need to be used in combination with other active drugs, in vitro resistance data suggests that there is not a particularly low barrier to resistance. At dosing 100mg twice daily, mean plasma concentrations at 12 hours produced drug levels over the IC95. Based on the results of this study, Phase 3 studies will go forward at 400mg BID dose. Lack of interactions with other drugs cleared by P450 pathway, or with food, is also important.

Although the FDA are fast-tracking the approval process for MK-0518, this is still very early data from a small number of patients. Other promising drugs have shown problems in Phase 3 studies due toxicity that only became apparent when studied in larger groups, and last years excitement over CCR5 inhibitors is tempered by later concerns in two of the three lead compounds. Nevertheless, other characteristics of MK-0518 suggest this may be appropriate for research into numerous strategies: treatment experienced patients, PEP, PrEP, and earlier initiation of treatment. Perhaps most importantly is an option for second-line therapy in resource-limited countries given the less complicated manufacturing process (and the potential to cost less than any protease inhibitor) and independence from ritonavir boosting.

An expanded access programme is scheduled to start in the US in September 2006, and EAP programmes are expected to start in Europe and the UK in the new few months.

For more details in the UK contact the medical information department at MSD on 01992-467272.

Patients can be registered for the expanded access programme at:


  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. Late breaker abstract THLB0214.
  2. Grinsztejn B et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 13 CROI Abstract 159LB. See HTB March 2006.

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