First-in-class HIV treatment gets green light

November 19, 2007

Raltegravir, a new drug that inhibits integrase, the enzyme responsible for the insertion of HIV DNA into human DNA, was granted accelerated approval by the FDA.

"The integrase enzyme is responsible for integrating the HIV viral DNA into the CD4 lymphocyte cell's own DNA," explained John M. Conry, Pharm.D., BCPS, associate clinical professor at St. John's University School of Pharmacy. "In other words, raltegravir stops HIV from inserting its genetic code into an infected cell, thereby preventing the virus from making new copies of HIV."

The agency approval was based on a 24-week analysis of HIV RNA viral load in patients taking raltegravir in combination with optimized background therapy (OBT). "The efficacy of raltegravir was demonstrated in BENCHMRK-1 and BENCHMRK-2 with statistically significant decreases in HIV viral load and increases in CD4 cell counts," remarked Conry. Furthermore, because raltegravir is in a new class of antiretroviral drugs, it seems to have almost no cross-resistance with the anti-retrovirals in older classes, he pointed out. "It provides a new alternative treatment for patients who are running out of options secondary to antiretroviral resistance."

"Raltegravir appears to be fairly well tolerated," Conry commented. There is a low potential for drug-drug interactions at this time and, based on data shown, it is not expected to affect the pharmacokinetics of drugs that are substrates of the major CYP 450 enzymes or p-glycoprotein, he added. The prescribing information does warn, however, that caution should be exercised when co-administering raltegravir with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (i.e., rifampin) due to reduced plasma concentrations of raltegravir.

Common adverse effects (incidence >10%) observed during clinical trials included nausea, headache, pyrexia, and diarrhea. In addition, creatine kinase elevations were also observed in subjects receiving raltegravir. "Myopathy and rhabdomyolysis have been reported, thus caution is warranted," explained Conry. Particular attention should be paid to patients with concomitant use of other medications known to cause this effect, he added. During the initial phase of treatment, patients should also be monitored for Immune Reconstitution Syndrome, an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus, which may require further evaluation and treatment.

With a low pill burden (one tablet twice daily) and no food restrictions, raltegravir may provide improved adherence compared with complicated regimens, believes Conry. "Adherence is an important factor since nonadherence is a cause of treatment failure and antiretroviral resistance," he said.

Merck has announced the wholesale acquisition cost of raltegravir to be $9,855 a year, or $27 per day and, according to the company, the price is in tune with available ritonavir-boosted protease inhibitors. The patient-assistance program, SUPPORT, will provide personalized support and patient advocacy regarding individual reimbursement issues. More information can be accessed at http://www.isentress.com/.

TIPS TO REMEMBER Isentress

• Isentress 400-mg tablets are pink, oval-shaped, film-coated, and are available in bottles of 60 tablets.

• Isentress can be taken with or without food.

• Safety and efficacy of Isentress has not been established in treatment-naïve adult patients or pediatric patients.

• Breast-feeding is not recommended for the patient taking Isentess.