Week 48 raltegravir results in treatment-naive phase II dose-finding study
3 September 2007. Related: Conference reports, Antiretrovirals, IAS 4th Sydney 2007.
Simon Collins, HIV i-Base
Martin Markowitz from the Aaron Diamond AIDS Research Centre presented 48-week results from the phase II raltegravir dose-ranging study in 198 treatment naive patients. The study included efavirenz as a control arm and all patients used background tenofovir plus FTC. [1]
Efficacy and safety results from the 24-week analysis of this study were presented at the Retrovirus conference earlier this year and, together will full study details, were reported previously in HTB. [2, 3]
The summary of the IAS presentation generally showed that the impressive week 24 results were maintained through to week 48.
Proportions of patients achieving viral reductions to <50 copies/mL at week 48 remained over 80%, and was 88% in the highest dose groups (see Table 1).
Table 1: Raltegravir (RAL) vs efavirenz in treatment naive patients at 24 and 48 weeks
| Treatment group (with TDF/3TC) | N | % pts <400 copies/mL | % pts <50 copies/mL | ||
|---|---|---|---|---|---|
| Week 24 | Week 48 | Week 24 | Week 48 | ||
| RAL 100mg BD | 39 | 95 | 97 | 87 | 85 |
| RAL 200mg BD | 40 | 85 | 85 | 85 | 83 |
| RAL 400mg BD | 41 | 98 | 98 | 93 | 88 |
| RAL 600mg BD | 40 | 95 | 90 | 95 | 88 |
| Efavirenz QD | 38 | 95 | 87 | 92 | 87 |
The side effect profile was similar in all groups, though raltevgravir had fewer CNS-related events, and a better lipid profile – with no effect on total cholesterol, LDL cholesterol or triglyceride levels.
In a second presentation in the same session, John Murray from the National Centre in HIV Epidemiology and Clinical Research, Sydney, presented an analysis of the viral decay kinetics seen with raltegravir. [4]
Nine days monotherapy showed no differences in early decline between difference doses studied. In combination therapy, the raltegravir arms showed a much faster viral load reduction to <50 copies/mL, compared to the efavirenz arm at day 15 (p<0.047), at day 29 (p<0.003), and at day 57 (p<0.006). Median second phase viral levels for the raltegravir groups were significantly reduced by 70% over the EFV group (p<0.0001). First phase decline involves the loss of productively infected cells with a half-life of 1.5 days, second phase is loss of long-lived cells with a half-life of 14 days.
Murray suggested two hypothesis that may explain this more rapid drop: 1) that second phase virus arises from cells newly infected by long-lived infected cells, or 2) that it arises from activation of latently infected cells with full-length unintegrated HIV DNA.
Cross-resistance between integrase inhibitors was a main focus at the International Resistance Workshop, that was held in Barbados earlier this year, and reported in the last issue of HTB. [5]
Limited data supporting the earlier cautions from in vitro research were presented by Edwin DeJesus in case studies of two patients who had failed virologically on Gileads investigational integrase inhibitor elvitegravir, and who were non-responders to subsequent use of raltegravir. [6]
A poster at the meeting also presented early information about a second generation integrase inhibitor (MK-2048) which has shown good pharmacokinetics in dog and rat studies and in vitro sensitivity against the N155S mutation that currently leads to cross-resistance between raltegravir and elvitegravir. [7]
Comment
As this issue of HTB went to press (5 September), the US FDA advisory committee recommended approval of raltegravir for treatment-experienced patients who have ongoing viral replication despite existing treatment.
Several documents relating to this hearing are available online and suggest a good safety profile, and that raltegravir crosses the blood-brain barrier – something that until now had not been clearly addressed. [8, 9]
References:
- Markowitz M, Nguyen B-Y, Gotuzzo E et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment HIV-1 infected patients: 48-week data. 4th IAS Conference, Sydney, 2007. Abstract TUAB104.
http://www.ias2007.org/pag/Abstracts.aspx?SID=48&AID=3027 - Integrase inhibitor MK-0518: early results show greater early potency than efavirenz. HIV Treatment Bulletin September 2006.
http://www.i-base.info/htb/v7/htb7-9/Integrase.html - Lipid profile of integrase inhibitor MK-0518: 24 week results compared to efavirenz in treatment-naive patients. IV Treatment Bulletin, October 2006.
http://www.i-base.info/htb/v7/htb7-10/Lipid.html - Murray JM, Emery S, Kelleher A et al. The integrase inhibitor raltegravir alters viral decay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication. 4th IAS Conference, Sydney, 2007. Abstract TUAB103.
http://www.ias2007.org/pag/Abstracts.aspx?SID=48&AID=4178 - Integrase inhibitors and resistance. HIV Treatment Bulletin, June/July 2007.
http://www.i-base.info/htb/v8/htb8-6-7/Integrase.html - DeJesus E, Cohen C, Elion R et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). 4th IAS Conference, Sydney, 2007. Abstract TUPEB032.
http://www.ias2007.org/pag/Abstracts.aspx?AID=3229 - Vacca J, Wai J, Fisher T et al. Discovery of MK-2048 subtle changes confer unique resistance properties to a series of tricyclic hydroxypyrrole integrase strand transfer inhibitors. 4th IAS Conference, Sydney, 2007. Abstract WEPEA088.
http://www.ias2007.org/pag/Abstracts.aspx?AID=3234 - Raltegravir FDA Safety Report (08/31/07)
http://www.natap.org/2007/HIV/083107_07.htm - Raltegravir FDA Clinical Development Summary (08/31/07)
http://www.natap.org/2007/HIV/083107_06.htm