HIV PEP drugs: Isentress® (Raltegravir) intergrase inhibitor

Isentress® is one of the newest classes of antiretrovirals, the intergrase inhibitors. This drug disables the HIV intergrase protein which is responsible for integrating the viral genome into the human chromosome and causing the chronic incurable infection. Developed by Merck and Co, it was approved for adult use in 2007 by the FDA and use in children as late as 2011. It has been shown to be the most highly effective anti-HIV drug in lowering viral load (numbers of virus in the blood).

Despite the drug’s effectiveness, it does have an Achilles heel. The intergrase protein is highly mutagenic and resistance can develop quickly meaning that Isentress® must be used in combination with other antiretrovirals to be effective. HIV PEP therapy at our clinic includes the use of Isentress® together with Truvada® – a pill made by Gilead Sciences containing Emtricitabine (Emtriva®) and Tenofovir (Viread®). This is currently our preferred PEP treatment combination.

Side effects

Isentress® has fairly mild side effect compared to many other antiretrovirals for most people. It is common to experience insomnia and the resulting tiredness as well as headaches, dizziness and nausea.

Less common side effects are stomach pains, depression including suicidal thoughts, hepatitis, kidney disease and weakness. Help should always be sought immediately if you are experiencing suicidal thoughts and if you start to experience the onset of hepatitis symptoms, most notably jaundice, dark urine, clay coloured stool and loss of appetite. You should be tested regularly for kidney health while taking PEP and it is important that you attend all tests as they will pick up problems before they become bigger. The rebound of hepatitis can happen when treatment stops due to the removal of suppression of HBV by Isentress®. Your doctor should be alerted if you have HBV so that your liver function can be safely monitored following cessation of treatment.

A rare and rather strange side effect of Isentress® is outbreaks of Herpes sores in those who suffer from genital herpes or cold sores and the occasional outbreak of shingles. It is not known what causes this, but is likely to be due to stress on the immune system. Inform your doctor if you suffer from herpes or cold sores or if you have had shingles in the past before starting this medication.

Like any medication, allergies are possible and can in extreme cases be life threatening. Seek emergency medical assistance should you find a rash in combination with fever, extreme tiredness, unexplained muscle or joint pains, sores in the mouth, swelling around the eyes or inside the mouth or difficulty breathing. Do not take any more of the medication if these symptoms appear until given the all clear by your doctor.


As with all PEP drugs, hepatitis or other liver conditions and any kidney conditions need to be closely monitored while taking Isentress®. It has not been shown one way or the other what effects it has on a growing foetus so inform your doctor if you are pregnant and Isentress® should only be taken if essential during pregnancy. There is no indication it is harmful to the baby, but not enough information to say that it isn’t. You should never breastfeed while on PEP, not only because the medication is transmitted through breastmilk but also to prevent transmission of HIV virus that has not been inactivated. PEP is not a cure for HIV, it inhibits the virus long enough for the immune system to respond and it doesn’t always catch it in time. You should behave towards others as if you were infectious until the PEP has been proven to have prevented a chronic infection.

There are indications that Isentress® can exacerbate rhabdomyolysis or myopathy as well as other conditions that increase the levels of creatine kinase in the blood. Inform your doctor if you suffer from any of these conditions and seek advice should you experience any unexplained muscle weakness or pain. As always these are not a full list of the side effects, should you experience anything that concerns you that appears to be linked to starting Isentress® speak to your doctor.

Drug interactions

There are few drugs that have a risk of negative interactions with Isentress®. One to watch for is Magnesium supplements. The magnesium or aluminium in these supplements can bind to the Isentress® and inactivate the drug. You should stop taking multi-vitamins or antacids when starting Isentress® treatment as many of these contain magnesium and/or aluminium.

There is some indication that the antibiotic rifampin may speed up the liver in clearing Isentress® from the body. You should try to ensure that you attend the same doctor while on PEP so that he or she is aware of all the medications you are taking. If you do need to see a different doctor make sure they are aware you are taking PEP. It may be that the doctor will have to change the prescribed dose of Isentress® while you are taking rifampin to ensure the levels are sufficient to inactivate any HIV virus.

Other drugs to watch for are any others that increase liver metabolism or those that raise the acidity of the blood, both may decrease the effectiveness of Isentress® and the active levels will need to be monitored while on these drugs.  It will inevitably mean more blood tests, but despite the inconvenience, it is better to have a host of blood tests over the 28 days of treatment than have to have constant blood tests for the rest of your life because a HIV virus slipped past the drugs and integrated.

You should advise your doctor of any herbal remedies or supplements you are taking before starting any medication. As Isentress® is a relatively new drug it is likely there are other drugs it will react with in a negative way that are not yet known. If you feel unwell after taking another medication in combination with Isentress® inform your doctor immediately. If that medication is non-essential stop taking it immediately. If it is essential seek urgent medical advice regarding how to proceed.

Additional information

As Isentress® has only been approved for human use for less than ten years there is still a good deal to learn about how exactly it acts on the virus. Studies have shown surprising results with Isentress® notably that while the intergrase was thought to only cause integration into the human genome, blocking it resulted in viral loads falling faster with Isentress® than with the nucleoside reverse transcriptase inhibitors or the protease inhibitors. As both of these alternatives directly impact on viral replication, it would suggest that the intergrase has a more essential role in HIV replication that previously thought.

Work on other viruses, notably Hepatitis B (HBV) and Epstin-Barr virus have shown that despite being designed for HIV, Isentress® may be effective against a much wider range of viruses. Like Viread, Isentress® can cause a rebound effect in HBV sufferers as it is believed to lower HBV loads which recover when PEP treatment is stopped causing a bout of acute hepatitis. While not approved for treatment of HBV there are clinical trials currently assessing its effectiveness against HBV and it may offer hope in future for HBV sufferers.

Epstine-Barr virus (EBV) is a member of the Herpesviridae family (Lymphcrytovirus Human herpesvirus 4) and causes glandular fever (also known as infectious mononucleosis, mono or the kissing disease). It is one of the most common viruses and as well as being known for causing post-viral chronic fatigue, it is less well known as a risk factor in various cancers, notably gastric cancer and a variety of blood cancers (lymphoma) and autoimmune diseases such as lupus, rheumatoid arthritis and multiple sclerosis. Preliminary clinical trials with Isentress® suggest that the drug may be successful in reducing the severity of EBV-associated multiple sclerosis. If trials prove successful, it will lead to a very exciting possibility of treatment for this horrific disease, and perhaps many others.

It is a wonderful example of cross-discipline drug development where eagle-eyed doctors noticed a correlation between use of a drug for one purpose and followed through with their observations. The result of which is a HIV drug that not only provides hope for those with HIV, but spreads out to potentially treat cancer and autoimmune disease as well.

Watch this space, very exciting developments going on.

For more information see:

WebMD – Isentress®

Isentress® product information.

Information on use of Isentress® in treatment of relapsing Multiple Sclerosis