Isentress Durability in Drug-Naïve HIV Patients

Isentress Continues to be as Effective as Efavirenz with Benefits

Sep 29, 2009

Isentress-based therapy maintains activity at 96 weeks in treatment-naïve HIV patients, comparable to efavirenz.. The benefits are improved side effect and lipid profiles

Isentress is a first-in-class integrase inhibitor, which is approved for use in both treatment-experienced and treatment-naive HIV infected patients (HIV patients who have not yet been treated with any antiretroviral drugs). Further study results for use in treatment-naive patients show that Isentress is as effective and durable as efavirenz, when each drug is used in combination with tenofovir/emtricitabine. However, Isentress has the additional benefits of improved side effect and lipid profiles.

Function of Integrase Inhibitors

Integrase inhibitors block the function of HIV integrase, which is responsible for insertion of the HIV viral DNA into a human cell's DNA, which is an early step in the lifecycle of HIV. As such, drugs that belong to this new class can block the HIV virus from replicating and infecting new cells.

Isenress and Treatment-Naïve HIV Patients

Isentress was first launched in 2007 for the treatment of HIV in treatment-experienced patients. In these patients, Isentress is used in combination with other HIV drugs in order to reduce viral load and improve immune system function (CD4 cell count). Isentress has also been investigated for use in treatment-naïve HIV patients, and the drug received approval for this indication by the FDA in July this year, while the EMEA granted this extended approval for European countries earlier this month.

Extended approval was based on 48 week data from the STARTMRK trial, which involved treatment-naïve HIV patients who had high initial levels of the virus (greater than 5,000 copies/mL). The trial compared twice-daily Isentress to once-daily efavirenz, when each drug was used in combination with tenofovir/emtricitabine. Tenofovir/emtricitabine is available as a once-daily single combination pill called Truvada, while efavirenz in combination with tenofovir/emtricitabine is available as a once-daily pill called Atripla; Atripla is currently stand-of-care for treatment-naïve HIV patients.

The marketing application also contained data from two other phase 3 trials where Isentress was studied in treatment-experienced HIV patients.

STARTMRK Trial 48 Week Results

In the STARTMRK trial, efavirenz-based treatment reduced HIV viral loads to undetectable levels (lower than 50 copies/mL) in 87% of patients compared with 82% of patients who received efavirenz-based therapy. Isentress-treated patients achieved a greater average increase in CD4 cell counts (189 cells/mm3) compared with the group who received efavirenz-based therapy (163 cells/mm3); however, the difference in the overall change from baseline levels for each group was not considered statistically significant.

Merck also reported that at 48 weeks of treatment, Isentress had similar effectiveness as efavirenz in several patient groups. Various sub-analysis of data showed that:

- Isentress reduced viral loads to undetectable levels in 96% of women compared with 93% of women who received efavirenz-based therapy. Increases in CD4 cell counts were also comparable, with Isentress-based therapy resulting in a rise of 170cells/mm3 compared with 168cells/mm3 for efavirenz.

- Isentress-based treatment reduced viral loads to undetectable levels in 91% of patients with initial viral loads that were greater than 100,000 copies/mL, compared with 89% of patients on efavirenz-based therapy. Increases in CD4 cell counts were also similar for this group of patients when treated with either Isentress or efavirenz (196 cells/mm3 vs. 192 cells/mm3)

- Isentress was also comparable to efavirenz at reducing viral loads in patients of various racial backgrounds.

STARTMRK Trial 96 Week Results

Merck has recently reported results for the ongoing STARTMRK trial after 96 weeks of treatment to show that Isentress can continue to suppress viral loads to undetectable levels in treatment-naïve patients, at a comparable level to efavirenz. Isentress-based therapy suppressed levels of the HIV virus to below 50 copies/mL in 81% of patients, which was comparable to the 79% of patients treated with the efavirenz-based regimen who achieved these levels. Improvements in CD4 cell counts were greater for patients treated with Isentress (240 cells/mm3 vs. 225 cells/mm3), but the difference was not statistically significant.

The Isentress-based regimen saw a lower impact on elevating lipid levels compared with the efavirenz-based regimen, which reached significance for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as triglycerides.

In addition, Isentress resulted in fewer side effects, with 47% of patient taking the Isentress-based combination reporting drug-related side effects compared with 78% on the efavirenz-based combination. The incidences of all most commonly reported side effects were higher in the efavirenz-treated group, except for respiratory, thoracic and mediastinal disorders, which saw a 4% greater incidence in Isentress-treated group.

Isentress Versus Efavirenz in Combination Treatment

Merck has shown that Isentress-based therapy can maintain viral load suppression and improvements in CD4 cell counts through to 96 weeks in treatment-naïve HIV patients. In addition, Isentress in combination with tenofovir/emtricitabine is as durable as efavirenz/tenofovir/emtricitabine, which is available as once-daily Atripla - the current standard-of-care for antiretroviral-naïve patients. A smaller phase 2 study has also demonstrated that efficacy can be maintained through to 144 weeks in this target patient pool.

The continued effectiveness of Isentress in treatment-naïve HIV patients is very important, since the development of resistance to antiretroviral drugs can severely limit their clinical effectiveness. While the durability is similar to that of efavirenz/tenofovir/emtricitabine, efavirenz in combination with tenofovir/emtricitabine has the benefit of improved side effect and lipid profiles. On the other hand, efavirenz/tenofovir/emtricitabine has the advantage of being available as the once-daily treatment, Atripla, while Isentress currently has to be dosed twice daily and in combination with another drug.

Further studies are underway investigating various combinations of antiretroviral drugs with efavirenz in comparison to the combination therapy found in Atripla, in order to determine the best regimen for Isentress in treatment-naïve HIV patients and differentiate this drug from the current standard-of-care.

Information in this article was obtained from the following press releases on Merck’s website:

Merck 2009, FDA Approves Expanded Use of ISENTRESS® (raltegravir) in Combination Therapy for Adult Patients with HIV-1 Infection to Include Patients Not Previously Treated with HIV Medicines, viewed September 28, 2009

The copyright of the article Isentress Durability in Drug-Naïve HIV Patients in Biotech/Pharmaceuticals is owned by Christine Redmond. Permission to republish Isentress Durability in Drug-Naïve HIV Patients in print or online must be granted by the author in writing.