POSITIVELY AWARE MARCH/APRIL 2011
brand name: Isentress
common name: raltegravir
class: Integrase inhibitor (integrase strand transfer inhibitor or INSTI)
manufacturer: Merck and Co. | www.isentress.com, (800) 622–4477
Standard dose: One 400 mg film-coated tablet twice a day, with or without food, with no dietary restrictions. Take missed dose as soon as possible, unless it is almost time for your next dose. Do not double up on your next dose.
AWP: $1,121.93 / month
Potential side effects and toxicity
Very tolerable, but most common are diarrhea, nausea, headache, and fever. Less common are abdominal pain, vomiting, fatigue, weakness, dizziness, and lipodystrophy. Other observations with unclear relationship to Isentress include cancer (new and recurrent, though most patients had other risk factors for cancer), low white blood cell count (neutropenia), low platelets, and elevated liver enzyme levels. 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; signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is initiated. Report symptoms of illness, such as shingles and TB, to a health care provider.
Potential drug interactions
Aptivus/Norvir can 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. Use caution with rifampin, which reduces plasma concentrations of Isentress; increase dose of Isentress to 800 mg twice a day. Prilosec (omeprazole) can increase concentrations of Isentress, but no dose adjustment is recommended. There is no interaction with methadone.
More information
U.S. HIV guidelines list Isentress along with a Truvada backbone as a preferred regimen for people taking HIV therapy for the first time. Isentress, the first drug in a new class called integrase inhibitors, continues to shine bright. Isentress is exciting for several reasons. Two years ago, Isentress did something no other HIV drug ever did: it dropped viral load to undetectable in more than a whopping 90% of treatment-experienced people, out to one full year. Undetectable viral load is more difficult to achieve in this population than in people on HIV therapy for the first time. The results were exciting, but from a small study. Isentress was taken with Prezista and Intelence, a novel, nuke-sparing combination. 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. The 96-week data show that Isentress continues to be effective with almost no side effects. The guidelines note drawbacks: twice-a-day dosing and a lower barrier to drug resistance than seen with boosted PIs. Greater tolerability, however, may help overcome those issues. Also, it’s only one tablet per dose, and does not have to be taken with the dreaded Norvir, the way PIs are. In fact, the SPIRAL study wanted to look at what would happen to patients with sustained virologic suppression on boosted protease inhibitors when switched to Isentress. The study of 273 people had 139 switch to Isentress and 134 to stay on their current Norvir-boosted protease inhibitor. It turns out that Isentress was non-inferior (a good thing) in terms of efficacy and resulted in a better lipid profile (lower cholesterol and triglycerides) after 48 weeks. The latest guidelines point out that two other studies showed increased risk of failure when switching from boosted PIs to Isentress in people with undetectable viral loads, and state that perhaps SPIRAL was successful because people had had undetectable viral loads for a longer time. The guidelines state that switching people from a boosted PI to Isentress should be done with caution, and avoided altogether in people who have HIV resistance to NRTI drugs unless they have fully active medications (to which their HIV is not resistant) to use. Moreover, the guidelines state that before prescribing Isentress, providers may want to order a resistance test that can measure INSTI resistance (standard tests cannot).
The community was hopeful when a once-daily vs. twice-daily Isentress in people on HIV therapy for the first time was in advanced (Phase 3) study. This would help adherence and make this an even more popular first line treatment. Unfortunately, the study was stopped short when once-daily Isentress was seen as inferior to twice daily. 83% of people taking once-daily Isentress reached undectable levels of HIV virus compared to 89% in the twice-daily arm. This was too much of a difference to continue the study. A deeper analysis shows that individuals with higher viral loads (greater than 100,000 copies/ml) were more prone to fail on the once-daily regimen (only 74% reached undetectable levels vs. 84% in the twice-daily arm). See package insert for more complete information on potential side effects and interactions.
Doctor’s comments
Isentress made a stunning entrance when it was first approved for use in treatment-experienced patients. Perhaps more than any other drug, it revolutionized so-called “salvage therapy.” In combination with other new or second-generation agents, it made it possible for just about anyone willing to swallow pills to have an undetectable viral load. The fact that it was virtually free of side effects or significant toxicity didn’t hurt, either. The combination of Isentress and Truvada was subsequently shown to be as effective as Atripla for initial therapy, but with fewer side effects and lipid elevations. Isentress/Truvada is now a preferred regimen for initial therapy in the guidelines, though it is the only one that requires twice-daily dosing. Hopes that it could be dosed once a day were dashed by a recent clinical trial that clearly showed better results with twice-daily dosing, especially in people with high baseline viral loads. This combination also has no clear advantage over Atripla from a resistance standpoint: integrase mutations can occur quickly when viral suppression isn’t maintained, and Isentress resistance is likely to result in cross-resistance to other integrase inhibitors in development. —Joel Gallant, MD, MPH
Activist’s comments
A lifesaver for many when it was the first integrase inhibitor introduced at about the same time as Prezista and Intelence, Isentress continues to be a versatile drug for both treatment-experienced and naïve patients. Hopes that it could be a once-a-day pill were dashed when study results showed that once-daily dosing was not as effective as twice-daily. Still, it remains a very effective and well tolerated drug, with as yet no challengers in its class. —Jeff Taylor
