Isentress

Integrase Inhibitor

Common Name: raltegravir (RAL, formerly MK-0518)

Brand Name: Isentress

Class: integrase inhibitor

Standard dose: One 400 mg film-coated tablet twice a day, with or without food. Take missed dose as soon as possible, but do not double up on your next dose.

AWP: $1,072.34 / month

Manufacturer contact: Merck and Co.,
www.Isentress.com, 1 (800) 622-4477

AIDSInfo:
1 (800) HIV-0440 (448-0440), www.aidsinfo.nih.gov

Potential side effects and toxicity: Very tolerable, but most common were diarrhea, nausea, headache, and fever. Less common were abdominal pain, vomiting, fatigue, weakness, dizziness, and lipodystrophy. Other observations with unclear relationship to Isentress include cancer (new and recurrent). Most patients had other risk factors for cancer, low white count (neutropenia), low platelets, and elevated liver enzymes. May cause elevated levels of a muscle enzyme (creatine kinase) on blood tests. Contact your health care provider if you experience unexplained muscle pain, tenderness, or weakness. May cause hypersensitivity (allergic reaction), anemia, neutropenia, and gastritis. Increases in ALT, AST, and total bilirubin, all signs of liver toxicity, seen in around 8% of people taking Isentress. Increases were more likely in people also infected with hepatitis B or C. Immune Reconstitution Inflammatory Syndrome (IRIS) may occur as the immune system regains strength; report symptoms of illness, such as shingles and TB, to health care provider.

Potential drug interactions: Isentress had an effect on the concentrations of Epivir and Viread. Rifampin reduces the concentrations of Isentress; caution should be used when coadministering. Aptivus/Norvir can also decrease the concentrations of Isentress, but no clinically significant interaction was observed from the clinical studies in patients receiving both drugs. Dose adjustment is not required. Reyataz and Reyataz/Norvir increase blood levels of Isentress, but no dose adjustment is recommended. Caution is advised in people taking medications that can cause muscle problems. Caution with rifampin, which reduces plasma concentrations of Isentress.

Tips: Isentress continues to be a star. The data is in accord with the advocate view that advanced patients are having dramatic results and almost no side effects. Many people on long-time therapy became undetectable for the first time. One doctor reported that patients at his clinic could not believe they had received Isentress instead of placebo during studies. Some HIV specialists switched patients off Fuzeon and on to Isentress. Several studies showed good results with this strategy. To join a once-a-day Isentress study, consult your doctor or visit www.benchmrk.com and click on QDMRK. There are hopes of Isentress replacing a boosted PI. Isentress is exciting for several reasons. This is one of the truly new drugs that advanced patients are in such desperate need of. Isentress doesn't have to be boosted with the dreaded Norvir like so many other new HIV drugs, has had no major interactions with other HIV drugs, and can be taken with or without food. A big plus: cholesterol and triglyceride blood levels have not been a problem with Isentress, out to 48 weeks results. It's shown good potency in early (two weeks) results in both people on therapy for the first time and those who were heavily treatment experienced, compared to the gold-standard Sustiva plus optimized background. The idea of such early and amazing potency -- never seen with an HIV drug before -- is exciting. An amazing number of people reached undetectable viral load in durable results: at 48 weeks, 64 to 71% of people on Isentress (depending on the dose used in study) had less than 400 viral load; 46 to 64% of them had less than 50. The majority of people with treatment failure, however, were those who had no other active drug to add along with Isentress. With so many newer HIV drugs on the market now (Prezista, Selzentry, Aptivus, Intelence, Fuzeon) that problem should be less common. The rate of side effects was similar to the study group taking placebo (both the placebo group and the Isentress group used an optimized background -- the best drug combination they could take). In data presented to the FDA for approval, the people taking raltegravir had more than twice the decrease in viral load than seen in the placebo (dummy pill) group (-1.85 vs. -0.84 log). This drug did its best when used with Fuzeon. It was not, however, tested with other newer drugs now available in the pharmacy. In vitro (test tube) cross-resistance has been observed to other integrase inhibitors under development, which could limit this class in the future. More research is needed in this area. Please see package insert for more complete potential side effects and interactions.

Doctor

Isentress (raltegravir) was approved (one tablet twice daily) for use in combination with other antiretroviral drugs in the treatment of HIV infection in 2007. It is approved only for those who have failed other antiretroviral therapy. Raltegravir is the first drug approved in a new class of antiretrovirals -- integrase inhibitors. The HIV integrase enzyme inserts the virus DNA into the host DNA. An antiretroviral agent inhibiting the action of this enzyme should have great value in the treatment of HIV infection (even beyond what we know now), and health care providers are excited by the potential of this drug. While the long term adverse effects of raltegravir are not known, it currently appears to be fairly well tolerated. Reports of significant depression with the use of the drug await further verification. We have noted some patients with dizziness (we have not seen depression) with the drug, but have not verified this. Efficacy of raltegravir in HIV-infected individuals naive to therapy has been demonstrated, but it is not yet approved for this use. Some of us haven't waited for this official approval! -- Frank M. Graziano, M.D., Ph.D.

Activist

Isentress, formerly known as MK-0518, is the first FDA-approved drug in this novel class. After reverse transcription of HIV viral RNA into DNA occurs, HIV DNA integrates into a healthy CD4+ T-helper cell's nucleus, and thus its DNA. Integrase inhibitors work by blocking the viral enzyme that assists in this process. Isentress' initial indication is for the treatment-experienced with multiple drug resistance. Isentress when taken with optimized background therapy (OBT: at least one other fully active drug) has been shown to work well and side effects seem minimal. Isentress does not require Norvir boosting, quickly lowers viral load, and has relatively few drug-drug interactions. The great hope for this drug is that it will work to lessen resistance to other drug classes. But therein lies the paradox. Resistance to the integrase class can develop quickly if not combined with other active drugs. The challenge: which drugs? New and noteworthy: Isentress recently received FDA-approved review status for treatment-naive patients. Hopefully, there will be an indication for initial therapy with treatment naives by this summer. -- Morris Jackson

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