Raltegravir (Isentress)

Maraviroc (Selzentry)

Etravirine (Intelence)

For the past decade, standard HAART has consisted of a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus a "backbone" of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

However the recent approval of novel classes of antiretroviral agents that attack HIV at different stages of its lifecycle allows for more flexibility in constructing potent regimens for highly treatment-experienced patients who have developed resistance to older drugs.

At the 9th International Congress on Drug Therapy in HIV Infection (HIV9) this week in Glasgow, Scotland, Italian researchers presented a study looking at a PI- and NRTI-sparing regimen consisting of 3 newly approved drugs: the integrase inhibitor raltegravir (Isentress), the CCR5 antagonist maraviroc (Selzentry), and the next-generation NNRTI etravirine (Intelence).

This study included 95 patients followed at San Raffaele Hospital in Milan who had been on failing triple-class regimens and were enrolled in Expanded Access Programs for raltegravir, maraviroc, and/or etravirine. Participants took the then-investigational drugs in the following regimens:

• Group 1: raltegravir + maraviroc + etravirine;

• Group 2: raltegravir + either maraviroc or etravirine + PI-sparing optimized background therapy (OBT);

• Group 3: raltegravir + either maraviroc or etravirine + PI-containing OBT, usually including ritonavir-boosted darunavir (Prezista);

• Group 4: raltegravir + PI-containing OBT, with neither maraviroc nor etravirine.

The patients were not randomized; regimens were chosen on the basis of treatment history, genotypic resistance testing, and HIV coreceptor use (CCR5 or CXCR4 tropism).

Most participants (75%) were men, the average age was about 45 years, the average duration of HIV infection was 16 years, and the average duration of antiretroviral drug exposure was 13 years. Across all groups, the baseline median CD4 count was around 275 cells/mm3, the nadir (lowest-ever level) was about 90 cells/mm3, and baseline viral load was about 4.2 log10 copies/mL.

Results

• At week 24, the following percentages of patients had HIV RNA < 50 copies/mL:

• Group 1: 86%;
• Group 2: 90%;
• Group 3: 79%;
• Group 4: 79%.

• CD4 cell increases in the 4 treatment arms were as follows:

• Group 1: 217 cells/mm3;
• Group 2: 115 cells/mm3;
• Group 3: 87 cells/mm3;
• Group 4: 106 cells/mm3.

• In a multivariable analysis, there were significant differences in CD4 cell recovery associated with treatment arm, baseline viral load, and HIV risk factor.

• CD4 cell gains were significantly higher in Group 1 compared with the other 3 arms (P = 0.05, 0.05, and 0.04, respectively).

• There was no independent effect on response according to patient age, sex, HIV risk factor, CD4 percentage, or CD4 cell nadir.

• Despite the high pill burden, raltegravir + maraviroc + etravirine was well tolerated overall.

Based on these findings, the investigators concluded that, "Salvage therapy with [raltegravir + maraviroc + etravirine] showed an excellent short-term CD4 recovery."

Reasons for these favorable results, they suggested, might include presence of multiple active drugs blocking consecutive targets of viral replication, the high doses of maraviroc required with this regimen, and avoidance of toxicities associated with ritonavir or NRTIs.

Raltegravir + Maraviroc Drug Interaction

In a related study presented last month at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) researchers performed a pharmacokinetic evaluation to assess drug interactions between raltegravir and maraviroc.

This open-label, multiple dose, fixed-sequence study enrolled healthy HIV negative adults; 17 completed the study. Dosing was as follows:

• Days 1-3: raltegravir 400 mg every 12 hours (q12h);

• Days 4-5: washout period;

• Days 6-11: maraviroc 300 mg q12h;

• Days 12-14: raltegravir 400 mg q12h + maraviroc 300 mg q12h.

Serial 12 hour pharmacokinetic parameters were assessed on day 3 (for raltegravir), day 11 (for maraviroc), and day 14 (for both drugs).

Results

• When co-administered, maraviroc and raltegravir areas under the time concentration curve (AUCt, a measure of total drug exposure between doses), maraviroc maximum concentrations (Cmax), and raltegravir C12 average concentrations were reduced relative to monotherapy.

• Maraviroc average concentrations (AUCt divided by 12) were > 100 ng/mL, which appears to be the threshold for increased risk of virological failure.

• Raltegravir C12 concentration values were reduced by an average of 28%.

Given these findings, the investigators concluded, "These changes are not likely to be clinically relevant and, thus, no dose adjustment is recommended."

A decrease in raltegravir C12 concentration of less than 60%, they stated, "is considered not clinically relevant." However, 2 participants in this analysis reached levels that low (decreases of 69% and 76%).

The researchers noted that in prior studies of HIV positive people receiving raltegravir, pharmacokinetic parameters varied considerably between patients and even within a single individual over time.

11/14/08

References

S Nozza, F Visco, A Soria, and others. Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected patients: raltegravir, maraviroc, etravirine. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):P45. November 10, 2008.

E Andrews, P Glue, R Labadie, and others. A Pharmacokinetic (PK) Study to Evaluate an Interaction Bewteen Maraviroc (MVC) and Raltegravir (RAL) in Healthy Adults. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-4055.