The online edition of The Lancet has published results from a forty-eight week Phase III study of previously untreated (treatment-naïve) HIV-infected patients which showed that ‘Isentress’® (raltegravir), Merck Sharp & Dohme Limited’s (MSD) first-in-class integrase inhibitor, was found to be as effective as efavirenz at suppressing viral load to undetectable levels (less than 50 copies/mL) when used in combination therapy.1

Additionally, at Week 48, patients taking raltegravir had significantly fewer side effects compared to the efavirenz group and there were greater increases in mean CD4 cell count recorded for the raltegravir group, although this was not statistically significant.1 Both raltegravir
and efavirenz were administered in combination with two other anti-HIV medicines, tenofovir and emtricitabine.1 The use of raltegravir in treatment-naïve patients is investigational and the product is not currently licensed in this patient group in Europe.

“These findings show that a raltegravir-based regimen was as effective as an efavirenzbased regimen, a standard first-line medication, in reducing viral load to undetectable levels and increasing CD4 cell counts in treatment-naïve patients,” said Mark Nelson, Consultant in HIV Medicine, Chelsea and Westminster Hospital, London. “This study suggests that raltegravir in combination therapy with other antiretroviral treatments may become an important new treatment option for a broader spectrum of patients, including those who have not been previously treated with HIV therapy.”

Raltegravir, the first and only approved integrase inhibitor, is currently approved in more than 80 countries across six continents for use in combination with other ARV agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of HIV-1 replication despite ongoing ARV therapy.2

MSD recently received a positive opinion from the European Union’s Committee for Medicinal Products for Human Use (CHMP) recommending expanded marketing authorisation for raltegravir in combination with other antiretroviral (ARV) medicinal products for the treatment of HIV-1 infection in all adult patients, including treatment-naïve and treatment-experienced patients.3

Raltegravir studied in a Phase III trial of more than 500 previously untreated HIV patients The Lancet reports findings from an ongoing multi-centre, double-blind, randomised, active-controlled Phase III trial of previously untreated HIV-infected patients called STARTMRK. In the study, 563 treatment-naïve, HIV-infected patients received either 400 mg raltegravir (n=281) orally twice daily or 600 mg efavirenz (n=282) orally once daily, in combination with tenofovir and emtricitabine. Suppression of viral load and increase in CD4 cell counts maintained through 48 weeks.

The data showed that HIV viral load was reduced to undetectable levels (less than 50 copies/mL) in 86 percent of patients treated with raltegravir compared to 82 percent of patients treated with efavirenz (p<0.0001). At week 48, patients taking raltegravir had a greater increase
in CD4 cell counts, an average increase of 189 cells/ L, while patients taking efavirenz had an average increase of 163 cells/ L. This difference though was not statistically significant.

Time to virologic response was significantly earlier for patients taking raltegravir compared to those taking the efavirenz regimen (p<0.0001).
Tolerability profile of raltegravir in STARTMRK study Drug-related adverse events of any severity occurred in fewer patients (44 percent vs.
77 percent; p<0.0001) treated with raltegravir. Raltegravir had minimal effect on lipid levels. Mean Changes in Lipid Concentrations from Baseline to Week 48 Raltegravir Mean Change Efavirenz Mean Change P Value
Total Cholesterol +0.55 mmol/L +1.82 mmol/L P<0.0001 HDL Cholesterol +0.23 mmol/L +0.56 mmol/L P<0.0001 LDL Cholesterol +0.33 mmol/L +0.89 mmol/L P<0.0002

Total: HDL -0.02 -0.01 P=.2924
Triglycerides -0.16 mmol/L 2.08mmol/L P<0.0001

In the study, the most commonly ( 2.0 percent in either treatment group) reported drugrelated clinical adverse experiences of moderate or severe intensity in patients receiving raltegravir and efavirenz, respectively, were headache (4 percent vs. 5 percent), nausea (3 percent vs. 4 percent), dizziness (1 percent vs. 6 percent), insomnia (4 percent vs. 3 percent), diarrhoea (1 percent vs. 3 percent), and fatigue (1 percent vs. 3 percent). Central nervous system (CNS) symptoms were reported significantly less frequently through Week 8 with the group receiving raltegravir compared to the group receiving efavirenz (20 percent versus 52 percent; p<0.0001). A significant treatment difference remained with the cumulative incidence of CNS events through Week 48 in the group receiving raltegravir compared to the group receiving efavirenz (26 percent versus 59 percent; p<0.0001).

Cancer was diagnosed in one patient taking the regimen with raltegravir and nine patients taking the regimen with efavirenz.

About Raltegravir

Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity.4 Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells.4 There are drugs
in use that inhibit two other enzymes critical to the HIV-1 replication process - protease and reverse transcriptase - but raltegravir is the only drug approved that inhibits the integrase enzyme.5 Raltegravir is a single 400 mg tablet taken twice daily without regard to food. Raltegravir does not require boosting with ritonavir.2

References

1. Lennox J, DeJesus E, Lazzarin A et al. Safety and Efficacy of Raltegravir-based versus Efavirenz-based Combination Therapy in Treatment-Naive HIV-1 Infected Patients. The Lancet. Early Online Publication, 3 August 2009doi:10.1016/S0140-6736(09)60918-1
2. Summary of Product Characteristics
3. CHMP for human use post-authorisation of positive opinion for ‘Isentress’. Available at:
http://www.emea.europa.eu/pdfs/human/opinion/Isentress_47115109en.pdf [Accessed on 03.08.09]
4 Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and Efficacy of the HIV-1 Integrase Inhibitor Raltegravir (MK-0518) in Treatment-Experienced Patients with Multidrug-Resistant Virus: A Phase II Randomised Controlled Trial. The Lancet 2007; 369:1261-1269.
5. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000; 287:646-50.

Source
Merck & Co