Early integrase inhibitor studies in treatment experienced patients raise hopes for new drugs in a new class

Simon Collins, HIV i-Base

Two oral presentations, both available online, indicated the potential of a new class of treatment.

Research into integrase inhibitors has been ongoing for over ten years, but until recently we had little idea of whether integrase could prove an effective target for viable treatment.

The compound furthest ahead in development is MK-0518 from Merck. It has shown in vitro activity against HIV that is resistant to current classes. As it is predominantly metabolised by glucuronidation (UGT1A1) and is not a potent inhibitor or inducer of CYP3A4, significant interactions with other antiretroviral through this pathway are less likely. It does not need ritonavir boosting and can be taken with or without food, but requires twice-daily dosing. Results from a 10-day monotherapy dose-ranging study in treatment naive patients showed viral load decreases of 1.7-2.2 log, and were reported at the EACS conference in Dublin last year and included in our coverage in the last issue of HTB.

At the retrovirus meeting Grinsztejn and colleagues presented 8-week data from an interim analysis of two sub studies from a dose-finding study in three-class experienced patients. [1]

Patients were randomised to 200, 400 or 600 mg MK-5018 bid, or placebo, all in combination with optimised background therapy. Sub studies stratified patients by use of either T-20 or atazanavir (n=116 without ATZ and 16 with ATZ). Atazanavir boosts MK-0518.

Median age was 44 years and the group was mainly male (10% women). Mean CD4 and viral load were 220 to 283 cells/mm3 and 4.6 to 4.8 log copies/mL, respectively. Participants had used ARVs for a median of 9-11 years. T-20 was used by 33 to 38% of patients. This was a very treatment experienced group with almost half having no sensitive drugs available to use in the optimised background treatment (OBT) regimen (see Table 1).

Table 1: PSS (phenotypic sensitivity score)

200mg 400mg 600mg placebo
N 40 42 42 43
0 to all ARVs* 40% 57% 50% 40%
0 to PI 98% 95% 88% 84%

*T-20 not included in PSS score

At week 16, 65% to 85% of patients in the three MK-0518 dosing arms had <400 copies/mL and 56% to 72% reached <50 copies/mL, compared to approximately 20% for each measure in the placebo group. From the limited data on the slide presentation, the majority of patients reached these levels by week 8.

The mean viral load reduction was about -2 logs for the MK-518 groups compared to just less than 1 log for the OBT arm. These reductions occurred within the first two weeks, and were sustained for the duration of follow-up (only 25-28 patients in each of the 3 study arms had reached week 16 at the time of the analysis).

Mean CD4 increase was +100 to +110 cells/mm3 for the 600mg and 400mg groups, and about +30 cells/mm3 for the 200mg dose and the placebo groups.

The safety profile of MK-0518 was similar to placebo with most clinical adverse experiences being mild to moderate and not showing a clear dose relationship (see Table 2). Drug-related serious side effects reported in the respective arms included: 1 case each of active pancreatitis after 2 doses, considered related to OBT (200mg); lacunar infarction by CT (placebo); lipoatrophy (blinded); anaemia, metabolic acidosis, renal insufficiency, death (blinded); and hepatomegaly tenderness and fever (600mg).

Table 2: Most common drug-related clinical side effects

Incidence >5% or 2 patients in at least 1 treatment group

MK-0518 Placebo
200mg 400mg 600mg
n 42 43 44 45
Diarrhea 5% 2% 2% 9%
Nausea 5% 5% 11% 11%
Fatigue 7% 0% 2% 2%
Headache 10% 0% 5% 4%
Pruritis 0% 2% 7% 0%

The first in vivo results of the integrase inhibitor in development from Gilead were also presented as a late-breaker. [2] GS-9137 (formally JTK-303) is an integrase inhibitor that needs to be taken with food to increase bioavailability and showed no dose limiting toxicity in rat and dog studies. DeJesus and colleagues randomised a mixed group of 40 treatment-naive and treatment-experienced (off treatment) patients to 10 days monotherapy (30 to active drug and 10 to placebo). Only one woman was enrolled in this study. Mean baseline CD4 and viral load were 442 cells/mm3 and 4.75 log copies/mL (range 3.69-5.73) respectively. 30% patients had viral load > 5.0 log copies/mL.

Impressive viral load reductions occurred in all arms that were significant compared to placebo (p<0.01), and are detailed in Table 3. Responses were related to steady state Cmin concentrations, and although all doses produced trough levels above the protein adjusted EC50 for wild-type virus, the 50mg arm boosted by 100mg ritonavir exceeded this by at least 20-fold. Viral load returned to baseline from day 11 to day 21, with lower doses producing a faster viral rebound.

Drug related adverse events occurring in >1 patient included fatigue, diarrhoea, headache and nausea, all generally mild and which resolved on stopping treatment. There were no serious or grade 4 side effects in the treated groups. Grade 3 lab abnormalities included an increase in grade 3 triglycerides (400mg BID), grade 3 amylase increase (50mg/RTV) and increases in AST, total amylase and creatinine kinase (placebo).

Table 3: Efficacy and safety after 10-day monotherapy

200mg twice daily 400mg twice daily 800mg twice daily 800mg once daily 5mg + 100mg RTV once daily placebo (inc n=2 +placebo/r
n 6 6 6 6 6 10
Median log10 HIV RNA change (range) -1.48 (-0.97, 2.10) -2.03 (-1.04, -2.44) -1.77 (-1.27, -2.66) -0.96 (-0.56, -1.41) -2.03 (-1.54, -2.38) -0.26 (-0.48, +0.05)
=1 log 3 4 6 6 6 0
=2 log 0 1 3 3 3 0
No. pts with side effects 3 3 5 2 4 8
No. pts with graded lab abnormalities 3 3 5 2 4 8
No. pts with grade 3 or 4 lab abnormalities 0 1 0 0 1 3

Based on the results of this study, GS-9137 will go forward into Phase II studies as a once-daily ritonavir-boosted compound.


These results are very encouraging, and generated a lot of interest at the meeting.

A poster at the conference showed that integrase inhibitors are potent substrates for P-glycoprotein (P-gp), a transporter protein that plays an important role in drug bioavailability.

This suggests that although interactions involving the CYP450 3A4 pathway is not implicated, drug interactions studies will still be needed with existing ARVs, in order to establish any clinically relevant pharmacological modulation of oral drug bioavailability and for drug penetration through blood-brain and blood-testis barriers. [3]


Unless stated otherwise, all references are to the Programme and Abstracts from the 13th Conference on Retroviruses and Opportunistic Infections, 5-8 February 2006, Denver, Colorado.

  1. Grinsztejn B, Nguyen BY, Katlama C et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Abstract 159LB.
  2. DeJesus E, Berger D, Markowitz M et al. The HIV integrase inhibitor GS-9137 (JTK-303) exhibits potent antiviral activity in treatment-naive and experienced patients. Abstract 160LB.
  3. Dupuis ML, Cianfriglia M, Costi R et al. HIV-1 Integrase Inhibitors Are Potent Substrates for the MDR1 Multidrug Transporter. Abstract 566.

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