Raltegravir (Isentress)

Summary

Raltegravir is a type of anti-HIV drug called an integrase inhibitor. Common side effects of raltegravir include diarrhea, nausea and headache. The dose of raltegravir used is usually 400 mg twice daily. Raltegravir can be taken with or without food.

What is raltegravir?

Raltegravir, sold under the brand name Isentress, belongs to a new class of anti-HIV (or antiretroviral) drugs called integrase inhibitors. Raltegravir is used in combination with other anti-HIV drugs to treat, but not cure, HIV.

How does raltegravir work?

Raltegravir is the first integrase inhibitor approved for the treatment of HIV. This drug works by interfering with an enzyme needed by HIV called integrase. Using raltegravir as part of combination therapy reduces HIV’s ability to infect cells and make copies of itself.

How do people with HIV use raltegravir?

Raltegravir is used in combination with several other anti-HIV drugs, usually nukes (nucleoside analogues), non-nukes (NNRTIs) and drugs from other classes, such as protease inhibitors. These combinations are called antiretroviral therapy, or ART. For more information on ART, see CATIE's A Practical Guide to HIV Drug Treatment.

For many people with HIV, the use of ART has increased their CD4 counts and decreased the amount of HIV in their blood (viral load). This reduces a person’s risk of developing life-threatening infections and allows them to stay healthy for longer. Neither raltegravir nor any other anti-HIV medication is a cure for HIV. It is therefore important that you do the following:

  • See your doctor regularly so that he or she can monitor your health.
  • Continue to practise safer sex and take other precautions to prevent passing HIV on to other people and to protect yourself from different strains of HIV and other germs.

Warnings

Because raltegravir is a relatively new medication (it was only approved in 2008), the full range of its side effects may not be known for many years.

1. Severe rash and allergic reactions

Severe and, in rare cases, life-threatening rash have been reported. If you develop a rash with any of the following symptoms, stop using raltegravir and contact your doctor immediately.

  • fever
  • feeling being generally unwell
  • extreme tiredness
  • muscle or joint aches
  • blisters or sores in your mouth
  • blistered or peeling skin
  • red or swollen eyes
  • swollen mouth or face
  • difficulty breathing

An allergic reaction to raltegravir can potentially lead to liver problems. Contact your doctor immediately if you have any of the following symptoms:

  • yellowing of the skin or eyes
  • dark or tea-coloured urine
  • pale-coloured stool
  • nausea or vomiting
  • loss of appetite
  • pain or tenderness on the right side below the ribs

2. Pregnancy and breastfeeding

Raltegravir has not been studied in large numbers of pregnant, HIV-positive women. Therefore, the manufacturer recommends that pregnant women not use this drug. If you are pregnant or plan on trying to get pregnant, talk to your doctor so that you can find medicines that are safe for you and your baby.

HIV-positive mothers on raltegravir should not breastfeed due to the serious adverse reactions raltegravir can cause in nursing infants and due to the possibility of HIV being passed from mother to child.

3. Other medicines

The manufacturer recommends that raltegravir be used cautiously if you are also taking drugs such as the antibiotic rifampin (used to treat tuberculosis). Levels of raltegravir may fall considerably when it is taken by people who are also taking rifampin.

4. Cancer risk

In the early stages of clinical trials with raltegravir, there were reports of an increase in cancers among raltegravir users. Concerned about this finding, researchers compared the number of cancer cases reported in several raltegravir trials. They found that there was no statistically significant difference in rates of cancer between people taking raltegravir and others who took placebos. This suggests that there is no significantly increased risk of cancer due to raltegravir.

People taking raltegravir will continue to be monitored for the development of cancer to ensure that raltegravir has no potential cancer-causing effects. For more information on cancer risk with raltegravir, see CATIE’s TreatmentUpdate 173.

Side effects

1. General

Raltegravir is generally well-tolerated. In clinical trials, raltegravir was used as part of combination therapy so it is difficult to know which side effects are caused by this drug. Here is a list of some symptoms reported by raltegravir users in clinical trials:

  • diarrhea
  • headache
  • nausea
  • tiredness/fatigue
  • upper respiratory tract infection
  • cough
  • fever
  • rash
  • muscle pain
  • stomach pain
  • dizziness
  • constipation
  • itching
  • difficulty sleeping

2. Hepatitis

Raltegravir has not been well studied in people co-infected with HIV and hepatitis B or C. In clinical trials, only about 16% of people taking raltegravir were co-infected with these viruses. Liver enzymes (AST and ALT) were somewhat higher in co-infected people with mild liver disease after taking raltegravir.

3. Lipodystrophy syndrome

HIV lipodystrophy syndrome is the name given to a range of symptoms that can develop after people take ART for some time. So far, there appears to be no link between raltegravir and lipodystrophy syndrome.

Symptoms of lipodystrophy syndrome include:

  • loss of fat just under the skin (subcutaneous fat) in the face, arms and legs
  • bulging veins in the arms and/or legs due to the loss of fat under the skin
  • increased waist and belly size
  • fat pads at the back of the neck (“buffalo hump”) or at the base of the neck (“horse collar”)
  • small lumps of fat in the abdomen
  • increased breast size (in women)

Together with these changes, your blood tests may indicate the following:

  • increased levels of fatty substances called triglycerides
  • increased levels of LDL-cholesterol (low-density lipoprotein), or “bad” cholesterol
  • increased levels of sugar (glucose)
  • increased levels of the hormone insulin
  • decreased sensitivity to insulin (insulin resistance)
  • decreased levels of HDL-cholesterol (high-density lipoprotein), or “good” cholesterol

The precise causes of HIV lipodystrophy syndrome are not clear and are difficult to understand because in some people with HIV there may be one or more aspect of the syndrome. For instance, some people may experience fat wasting, others fat gain, and others may experience both fat wasting and gain. What is becoming increasingly clear is that increases in a person’s levels of glucose, cholesterol and triglycerides over a period of several years can increase a person’s risk of diabetes and cardiovascular disease. So far, however, the many benefits of ART are much greater than the increased risk of cardiovascular disease and other side effects.

Maintaining a normal weight, eating a healthy diet, exercising regularly and quitting smoking are all important to help you reduce your risk of diabetes, heart disease and other complications. Regular visits to your doctor for checkups and blood tests are a vital part of staying healthy. If necessary, your doctor can prescribe lipid-lowering therapy.

Researchers are studying the lipodystrophy syndrome to try to discover how it might be avoided or minimized. To find out more about options for managing lipodystrophy syndrome, see CATIE's A Practical Guide to HIV Drug Side Effects.

4. Depression

According to regulatory authorities in the European Union as well as doctors in British Columbia, there have been reports of pre-existing depression worsening and of some people on raltegravir considering suicide. If you have been depressed in the past or think you might be depressed, let your doctor know.

5. Muscle weakness

There have been rare reports of cases of raltegravir-associated rhabdomyolysis—the breakdown of muscle tissue leading to muscle weakness. This rare problem may occur with all integrase inhibitors including dolutegravir and elvitegravir (in Stribild).

Muscles are highly active tissues, which require a lot of oxygen. They contain a protein called myoglobin that captures oxygen from the blood and helps to bring this gas to parts of the muscle that burn fuel to release energy. When muscles are damaged they release myoglobin into the blood. This protein and the products into which it is broken down can—in large amounts—cause kidney dysfunction.

Rhabdomyolysis can occur under the following circumstances:

  • alcoholism
  • serious accidents where tissues are compressed (crush injuries)
  • exposure to stimulants such as amphetamine and methamphetamine, cocaine, ecstasy and excessive caffeine
  • inherited muscle disorders
  • heat stroke
  • muscle injury arising from veins being blocked by blood clots
  • lower-than-normal levels of phosphorus in the body
  • seizures
  • very intensive and exhaustive exercise
  • chills
  • many medicines have been associated with rhabdomyolsis but one class stands out: statins (a group of drugs used to treat high cholesterol levels)

Rhabdomyolysis may not initially cause symptoms but the following signs may appear later:

  • dark-coloured urine
  • decreased production of urine
  • fatigue
  • stiff or aching muscles
  • tender muscles
  • painful joints
  • seizures

If fatigue is bothersome or persistent or any of the above listed side effects appear, speak to your doctor right away.

Blood tests may reveal abnormal levels of an enzyme called creatine kinase. Levels of the waste product creatinine may also be abnormal.

In some cases, nurses may provide intravenous saline solution to hydrate the body. This solution, in cases of rhabdomyolysis, may also be rich in bicarbonate to help increase the production of urine and accelerate the removal of myoglobin.

In very severe cases of rhabdomyolysis, dialysis (artificial filtration of the blood) may be necessary to remove myoglobin and other proteins temporarily.

Some people quickly regain their energy after being treated for rhabdomyolysis, while others can have fatigue and muscle aches for several months after treatment.

Drug interactions

Always consult your doctor and pharmacist about taking any prescription or non-prescription medication, including over-the-counter medicines, herbs, supplements and street drugs.

Some drugs can interact with raltegravir. An interaction may increase or decrease the amount of raltegravir you have in your body. Increased drug levels can cause you to experience more side effects or make pre-existing side effects worse. On the other hand, if drug levels become too low, HIV can develop resistance and your future treatment options may become more limited.

If you must take a drug that could potentially interact with raltegravir, your doctor can do the following:

  • adjust your dose of anti-HIV drugs or other medications; or
  • prescribe different anti-HIV drugs for you.

Drug interactions with raltegravir

Raltegravir can interact with the antibiotic rifampin/rifampicin, which is used to treat tuberculosis (see Warnings). Note that this list is not exhaustive.

Resistance, cross-resistance and treatment interruption

Over time, as new copies of HIV are made in the body, the virus changes its structure. These changes, called mutations, can cause HIV to resist the effects of anti-HIV drugs, which means those drugs will no longer work for you. Combining raltegravir with at least two other anti-HIV drugs delays the development of drug resistance.

To reduce the risk of developing drug resistance, all anti-HIV drugs should be taken every day exactly as prescribed and directed. If doses are delayed, missed or not taken as prescribed, the level of raltegravir in the blood may fall too low. If this happens, the HIV in your body can become resistant to the medication. If you find you are having problems taking your medications as directed, speak to your doctor, nurse or pharmacist about this. They can find ways to help you.

When HIV becomes resistant to one drug in a class, it sometimes becomes resistant to other drugs in that class. This is called cross-resistance. There are other integrase inhibitors in development, one of which is elvitegravir. If your HIV becomes resistant to raltegravir, it will also likely become resistant to elvitegravir.

Feel free to talk with your doctor about your current and future treatment options. To help you decide what these future options might be, at some point your doctor can have a small sample of your blood analyzed to test for resistance. Should the HIV in your body become resistant to raltegravir, your doctor can recommend a new treatment combination for you.

Dosage and formulations

Raltegravir (Isentress) is available in 400 mg tablets. The drug may be taken with or without food. The usual dose of raltegravir used in adults with HIV is 400 mg twice daily.

Formulations can change and dosages may need to be customized. All medications should always be taken as exactly as prescribed and directed.

Availability

Raltegravir is licensed in Canada for the treatment of HIV infection in adults in combination with other anti-HIV drugs. Your doctor can tell you more about the availability and coverage of raltegravir in your region. CATIE’s online module Federal, Provincial and Territorial Drug Access Programs also contains information about Canadian drug coverage.

 

References

Anderson MS, Kakuda TN, Hanley W et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrobial Agents and Chemotherapy. 2008 Dec;52(12):4228–32.

Cooper DA, Steigbigel RT, Gatell JM et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. New England Journal of Medicine. 2008 Jul 24; 359(4):355–65.

DeJesus E, Cohen C, Lennox J et al. Metabolic profiles and body composition changes in treatment-naïve HIV-infected patients treated with raltegravir 400 mg twice-daily vs. efavirenz 600 mg each bedtime combination therapy: 96-week follow-up. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco, U.S. Abstract 720.

DeJesus E, Rockstroh J, Lennox J et al. Raltegravir-based therapy demonstrates superior virologic suppression and immunologic response compared with efavirenz-based therapy with a favourable metabolic profile, through four years in treatment-naïve patients: 192-week results from STARTMRK. In: Program and abstracts of the 49th Meeting of the Infectious Disease Society of America, 20-23 October 2011. Abstract 30523.

Goethals O, Clayton R, Van Ginderen M et al. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. Journal of Virology. 2008 Nov;82(21):10366–74.

Gotuzzo E, Nguyen B-Y, Markowitz M et al. Sustained antiretroviral efficacy of raltegravir after 192 week of combination ART in treatment-naïve HIV-1-infected patients. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco, U.S. Abstract 514.

Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. AIDS. 2008 Sep 12;22(14):1890–2.

Iwamoto M, Wenning LA, Mistry GC et al. Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. Clinical Infectious Diseases. 2008 Jul 1; 47(1):137–40.

Iwamoto M, Wenning LA, Petry AS et al. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrobial Agents and Chemotherapy. 2008 Dec;52(12):4338–43.

Merck Frosst Canada. Isentress (raltegravir). Product monograph. 30 April, 2010.

Rockstroh J, Teppler H, Zhao J et al. Hepatic safety and efficacy of raltegravir in patients co-infected with HIV and HBV or HCV. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco, U.S. Abstract 662.

Roquebert B, Damond F, Collin G et al. HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro. Journal of Antimicrobial Chemotherapy. 2008 Nov;62(5):914–20.

Temesgen Z, Siraj DS. Raltegravir: first in class HIV integrase inhibitor. Therapeutics and Clinical Risk Management. 2008 Apr;4(2):493–500.

Wenning LA, Friedman EJ, Kost JT et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrobial Agents and Chemotherapy. 2008 Sep;52(9):3253–8.

Author(s): Hosein SR

Published: 2015