Raltegravir (RAL) is a medication in the class of drugs called “integrase strand transfer inhibitors” (INSTI), which stop HIV from making copies of itself later in its life cycle. It also goes by the brand names “Isentress” and “Isentress HD.” The Food and Drug Administration (FDA) originally approved Isentress as a part of antiretroviral (ARV) therapy in 2007; Isentress HD was approved by the FDA in 2017.
What are the different forms of raltegravir, and how are they taken?
There are two different forms of raltegravir in the U.S.:
Isentress – 400 mg tablets, red ovals with “227” printed on one side. Take one pill twice a day. For both treatment-naive and treatment-experienced patients.
Isentress HD – 600 mg tablets, yellow ovals with “242” printed on one side. Each day, take two pills at once. For treatment-naive patients and patients who have been virologically suppressed on an initial regimen of RAL 400 mg twice a day.
How often is raltegravir taken?
Raltegravir can be taken either twice daily or once daily, depending on the form, with or without food.
Isentress (also known by its generic name, raltegravir, or RAL) was the first medication in the integrase inhibitor class to be FDA-approved as part of a comprehensive HIV treatment regimen.
Isentress is currently listed as part of a recommended initial combination antiretroviral (ARV) treatment regimen for people who have never taken HIV medications before, according to official U.S. health department guidelines. It is recommended to be part of a three-drug regimen, along with:
Either Emtriva (emtricitabine, FTC) or Epivir (lamivudine, 3TC) as the second drug.
Either Viread (tenofovir disoproxil fumarate, TDF) or TAF (tenofovir alafenamide) as the third drug.
A Brief History of Isentress
When RAL was approved in 2007, it was a watershed moment in HIV treatment. It was the first of the integrase inhibitor (a.k.a. INSTI) class of medications. It offered new hope to people living with HIV who had developed resistance to, or were suffering side effects from, medications in other classes of ARVs.
Early studies found that people taking RAL had higher increases from baseline CD4 counts and better viral suppression when compared with people on the NNRTI Sustiva (efavirenz, EFV). RAL became a stable part of many initial regimens and a switch option for others. However, the twice-a-day dosing became problematic over the years, as more single tablet regimens (STR) and once-daily dosing regimens became available, eventually becoming a preferred option for many people.
To meet this need, a once-daily formulation of RAL, Isentress HD (two 600-mg tablets), was created and found to be equally efficacious at maintaining viral suppression and raising CD4 counts compared with the 400 mg twice-a-day version. Isentress HD was approved by the FDA in 2017, a full decade after the original was put on the market.
Does Isentress Work as Well as Other HIV Integrase Inhibitors?
Can Isentress match the HIV-fighting potency of newer INSTIs like Vitekta (elvitegravir, EVG), Tivicay (dolutegravir, DTG), or bictegravir (BIC)?
The short answer to that question is yes.
Before DTG was approved by the FDA in 2013, studies were conducted directly comparing DTG 50 mg daily with RAL 400 mg twice a day, which found them to be equally effective in sustaining viral suppression, with a very similar low risk of potential side effects. The question of whether RAL performs as well as the other INSTI medications with regard to viral suppression has never been in doubt. It absolutely has a similar level of effectiveness in this regard.
Both formulations of raltegravir, however, may have some disadvantages compared with other INSTI-based regimen options.
First, patients and providers frequently desire regimens with a low pill burden, notably a single-tablet regimen that only needs to be taken once daily. The original 400 mg tablet version has always been twice-a-day dosing—meaning folks have to take it with breakfast and again at dinner, or approximately 10 to 12 hours apart.
Even with the newer RAL HD version that was approved in 2017, while it can be dosed once daily, it requires taking two pills plus being combined with other medications.
Some may ask, “What’s the big difference between one pill a day and two to three pills once a day?” Psychologically, there is a difference for many people living with HIV, and the ease and simplicity of only having to ingest one pill, once daily, and its positive impact on adherence should never be underestimated. People do not like ingesting pills, period. You give them more to take, you may see reduced adherence.
In addition, RAL has never been combined with other medications in a STR format, which puts it at a considerable disadvantage compared with other ARV regimens.
A second barrier to more widespread acceptance and usage of RAL has been its resistance profile. Relatively speaking, HIV resistance to RAL does not happen often, but viral mutations to the INSTI class tend to reduce viral susceptibility to RAL and EVG the most, while sparing other INSTI medications like DTG, bictegravir (BIC), and cabotegravir (CAB), due to their relative durability and high genetic barrier to resistance.
Early reports of RAL resistance emerged in the late 2000s, which over time not only drove the field toward prescribing newer-generation INSTI medications like DTG and BIC, but also toward daily dosing and single-tablet regimens. This made it more difficult for RAL to be considered a first-choice treatment option for people with a new HIV diagnosis.
How to Take Isentress
Isentress is FDA-approved in the United States to be taken as one 400-mg tablet twice a day, with or without food. Isentress HD is FDA-approved in the United States to be taken as two 600-mg tablets, once daily, also with or without food.
As with other antiretrovirals, some may find that taking RAL with food is easier on the stomach.
The patent for RAL doesn’t expire for a few more years, so if you have health insurance, monthly copays for either version of raltegravir can typically run between $30 and $50, depending on the plan.
You should always check to see if your insurance can do a three-month supply, which may reduce the cost more. Additionally, you may qualify for cost-sharing assistance provided by the manufacturer.
If you don’t have insurance or your insurance won’t cover the majority of raltegravir’s cost (you are “underinsured”), there is a patient assistance program that can help reduce or eliminate the cost, depending on your financial situation.
Side Effects of Isentress
One of the upsides of RAL is that it has always been well tolerated, with relatively mild symptoms like headache, nausea, or diarrhea being reported.
When considering side effects, use the general rule of thumb of “the two-week rule”—when starting your HIV treatment regimen, give your body about two weeks for it to get adjusted to the medication.
Sometimes, symptoms like rashes, mild fever, or joint pain may happen. This could be related to the medication working and your immune system getting stronger as a result—manifesting as these symptoms, often called “immune reconstitution syndrome” by medical professionals. Keep in touch with your medical team and let them know as you move forward.
If, however, after a couple of weeks, you are still having bothersome symptoms or they are progressing, let someone from your medical team know so that you can schedule a virtual or in-person meeting to discuss. In this day and age, we have varying options for HIV treatment, and it is possible that even if a medication worked well for one of your friends, that doesn’t necessarily mean that your body will respond to it in the same way. Speak up, let your provider know, and discuss whether they recommend labs or switching up your regimen altogether.
Interactions Between Isentress and Other Drugs
Raltegravir has always had few, if any, drug interactions. It also does not require a boosting medication in it (e.g., cobicistat or ritonavir), which can increase the likelihood of these events happening. RAL has been found to be remarkably safe to be combined with almost all medications.
What’s the Verdict on Isentress?
RAL, the first of the INSTI-class medications to be FDA-approved for treatment of HIV, has been around since 2007 in its original twice-daily indication and since 2017 in its reformulated once-daily dosing formulation.
It is a safe and efficacious medication that can be combined with other HIV meds to form a complete ARV regimen, particularly for those who have not taken ARVs before, but also as part of a switch or “salvage” regimen if resistance develops to other medications.
Unfortunately, with the demand for STRs and its lower genetic barrier to resistance, RAL has been left behind in favor of newer INSTIs that either have a higher genetic barrier to resistance or have been combined with other medications in an STR.
RAL’s status as the abandoned child in the INSTI family may be a bit harsh. It is still a potent medication, and when combined with NRTIs, it is equally efficacious at maintaining viral suppression when adhered to properly, despite its relative lower genetic barrier to resistance when compared to the other INSTI medications.
There are many people who don’t mind or even prefer twice-daily dosing, as it helps them remember to take their medications with other twice-daily tasks. Some people prefer to use stand-alone drugs in combination with each other for better individual control, which is impossible with an STR, and many people living with HIV do take multiple medications and are accustomed to taking pills more than once daily.
There is a reason why RAL has remained on the recommended list of initial regimens for people living with HIV for so many years. While it may not be as sleek and glossy as the newest available STR, we should put some respect on its name and consider RAL as a viable option.