Antiretroviral Drug Types
Nucleoside reverse transcriptase inhibitors (NRTIs)
Nucleoside reverse transcriptase inhibitors, also called nucleoside analogs or nucleosides, interfere with the life cycle of HIV by preventing the transcription of viral RNA into DNA.
Most 3- and 4-drug regimens involve 2 nucleoside analogs, chosen on the basis of convenience, potential side effects, and patient preference. Certain drugs should not be used together because of the way they interact. For example, idovudine and stavudine should not be used together, and zalcitabine should not be combined with didanosine, stavudine, or lamivudine.
Drug studies are a very active area of HIV/AIDS research, and information is updated continually. It is important for patients to find a health care provider who specializes in HIV/AIDS medicine and knows about current clinical studies. Patients who are on antiretroviral therapy must be followed closely for treatment of related side effects.
Nucleosides can cause lactic acidosis (severely elevated blood lactate level) and liver enlargement (hepatomegaly; a rare but very serious side effect that can result in death). Lactic acidosis occurs more often in women and causes fatigue, belly pain, and shortness of breath. Nucleosides should be used with caution in patients who are at risk for liver disease, and treatment should be stopped if there is any indication of lactic acidosis or liver damage. Obesity increases the risk for side effects.
In most cases, nucleosides are combined with one other nucleoside plus either a non-nucleoside or protease inhibitor. NRTIs include the following:
- Zidovudine, azidothymidine (AZT, ZDV; Retrovir®)
This medication was the first FDA-approved antiretroviral drug and was the first ray of hope in the AIDS epidemic. A pivotal 1987 study showed how 6 months of AZT treatment could dramatically decrease AIDS deaths.
Initially, AZT was used alone. Today, like all nucleosides, AZT is used with 2 or more other antiretroviral medications. It is usually combined with lamivudine, didanosine, or zalcitabine. AZT should not be combined with stavudine.
The usual dose of AZT is one 300 mg pill twice a day, taken with or without food. AZT is also combined with lamivudine in a single pill called Combivir®, which is also taken twice a day. A second combination pill, Trizivir® contains abacavir, lamivudine, and zidovudine.
Side effects, which may include fatigue, nausea, and headache, usually improve or disappear a few days to a few weeks after starting therapy. AZT is sometimes associated with a decrease in the number of red blood cells (anemia) and prolonged use can lead to myopathy.
- Didanosine (also known as ddI; Videx®, Videx EC®)
Didanosine, which was approved by the FDA for the treatment of AIDS in 1991, usually is combined with AZT, stavudine, or lamivudine. It is sometimes combined with the anticancer drug hydroxyuria, which increases its effectiveness and side effects. This combination should be used with extreme caution.
The usual dose of didanosine is two 200 mg pills per day or one 400 mg daily, taken on an empty stomach. The pills have to be chewed or crushed and dissolved in water. A newer form of swallowable didanosine (Videx EC) is also available.
Side effects or didanosine include upset stomach and diarrhea. It can also cause painful neuropathy and pancreatitis (inflammation of the pancreas). Pancreatitis is a serious, potentially life-threatening complication that is more likely to develop in patients who have advanced HIV infection. If there are any signs of pancreatitis, this drug should not be used.
- Zalcitabine, dideoxycytidine (Hivid®)
This medication (also known as ddC) is the third nucleoside drug approved for the treatment of AIDS and usually is combined with AZT. The usual dose is 0.375–0.75 mg three times a day, taken with or without food.
Main side effects of zalcitabine are severe peripheral neuropathy; oral and, to a lesser extent, esophageal ulcers; and, rarely, pancreatitis. Neuropathy, which can be irreversible, occurs as a side effect in as many as one-third of all patients with advanced HIV/AIDS. If numbness, burning, tingling, or pain progresses beyond moderate discomfort, the drug should be discontinued. Zalcitabine should be used with extreme caution in patients with a history of neuropathy.
If there are signs or indications of pancreatitis, the drug should be stopped. In rare cases, liver failure and death have occurred, possibly due to underlying hepatitis B.
Three-time daily dosing and the high incidence of neuropathy have made zalcitabine a second- or third-choice medicine in the treatment of HIV.
- Stavudine (Zerit®)
Stavudine (also known as d4T) is the fourth nucleoside drug approved for the treatment of AIDS and is usually combined with didanosine and lamivudine. It should not be used with AZT because those two drugs work against each other.
The usual dose is one 30 or 40 mg pill twice daily, taken with or without food. The main side effect is neuropathy and it should be used with caution when combined with didanosine or zalcitabine, because those drugs also cause neuropathy. Neuropathy is more likely to develop in people with advanced HIV/AIDS. If a patient feels any symptom of neuropathy, they should tell their physician. Rarely, stavudine causes headaches or stomach upset.
- Lamivudine (Epivir®)
This drug (formerly 3TC), which was approved in 1995 to treat AIDS, is usually combined with AZT, abacavir, stavudine, or didanosine. The usual dose is one 150 mg pill twice daily, taken with or without food. Some studies show that the entire 300 mg dose can be taken once a day. Lamivudine is combined with AZT in a single pill called Combivir, which is taken twice a day. A second combination pill, Trizivir is also available. It contains AZT, lamivudine, and abacavir.
Lamivudine has very few side effects. Pancreatitis is a potentially fatal risk in pediatric patients. If a child has a history of pancreatitis or other significant risk factors for pancreatitis, the drug should be used with caution. If signs or symptoms of pancreatitis develop, lamivudine should not be used.
- Abacavir (Ziagen®)
Abacavir was the sixth nucleoside drug approved to treat HIV infection and was approved in 1998. Studies have shown that it is 5 to 10 times more potent than the other nucleosides. It is especially effective when used with AZT and lamivudine plus a protease inhibitor or non-nucleoside.
The usual dose of Abacavir is one 300 mg pill twice daily, taken with or without food. A second combination pill, Trizivir, is also available. It contains contain AZT, lamivudine, and abacavir.
In clinical studies, about 5 percent of people who take abacavir develop a hypersensitivity reaction that may be fatal. This reaction causes fever, nausea, vomiting, diarrhea, upset stomach, skin rash, body aches, and fatigue; usually develops within the first 6 weeks of treatment; and gets worse with every dose. If a patient develops hypersensitivity, he or she must contact to his or her physician immediately, stop taking the drug, and never take it again.
Because of the serious, possibly fatal consequences of a hypersensitivity reaction, it is important for patients who are taking abacavir to be closely monitored by a health care practitioner.
- Tenofovir disoproxil fumarate (Viread®)
This nucleoside, which is also called TDF, was approved in 2001 to treat HIV/AIDS. A combination pill, Truvada® is also available. It contains tenofovir and emtricitabine.
This drug is approved to treat HIV-1 infection in adults. It is taken as a tablet once a day, with or without food, and is used in combination with other antiretrovirals. Common side effects include nausea, vomiting, and diarrhea. Viread may cause serious liver or kidney problems and lactic acidosis (severely elevated blood lactate level), and may worsen hepatitis B infections.In January 2012, an NIH study indicated that vitamin D supplements may help prevent hormonal changes and reduce the risk of bone loss in young adults being treated with tenofovir. A 2-year follow-up study is planned.
- Emtricitabine (FTC, Emtriva®)
This drug received FDA approval in July 2003. It is also available in a combination pill, Truvada®, which contains tenofovir and emtricitabine. Emtriva should not be used with some other antiretrovirals (e.g., Atripla, Combivir, Epivir, Epzicom). It is available in tablets and an oral solution, and is used to treat children and adults. Side effects include headache, nausea, vomiting, and skin rash. This drug can also cause lactic acidosis and severe liver and kidney problems.
- Abacavir and lamivudine (Epzicom®)
This NRTI was approved in 2004 to treat HIV/AIDS in adults. It is used in combination with other antiretroviral drugs and can be taken with or without food and liquids.
Patients who have experienced a hypersensitivity reaction to abacavir should not take Epzicom. This drug may cause lactic acidosis and severe liver and kidney problems.
In August 2011, Complera was approved to treat HIV-1 infection in adults who are just starting antiretroviral therapy. Complera is a fixed-dose-combination mediation that contains emtricitabine, rilpivirine and tenofovir DF. The recommended dosage is one tablet, once a day, taken orally with food.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Non-nucleoside analogs interfere with the life cycle of HIV by preventing the transcription of viral RNA into DNA. There is no "best" non-nucleoside. As of January 2008, the FDA-approved non-nucleosides include nevirapine, delavirdine, efavirenz, and etravirine. Because resistance develops rapidly when non-nucleosides are used alone, they should always be used with other antiretrovirals. Patients who are taking any type of antiretroviral drugs must be followed closely by a health care professional for treatment-related side effects.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) include the following:
- Efavirenz (Sustiva®)
Efavirenz is the only non-nucleoside recommended by the U.S. Department of Health and Human Services to be used as a first-line treatment, with two nucleosides, in patients starting antiretroviral therapy. The usual dose is three 200 mg pills at bedtime, taken with or without food.
Side effects, which occur in about half of all patients who take this drug, include dizziness, poor concentration, confusion, abnormal dreams, depression, and drowsiness. These effects usually improve as therapy continues and typically last only about 2 to 4 weeks.
About 25% of adults and 40% of children who take efavirenz develop a skin rash within the first couple of weeks of treatment. The rash typically lasts about 2 weeks and is usually treatable. If the rash is severe, the drug should be discontinued.
Patients with a known or suspected history of hepatitis B or C should be monitored carefully while taking efavirenz. There appears to be an association, though not necessarily causal, between this drug and hepatitis. Due to a risk for birth defects, women who are pregnant or planning on becoming pregnant should not take efavirenz.
- Nevirapine (Viramune®)
Nevirapine is especially effective for patients who have lower-than-average HIV viral loads before starting treatment. The usual dose is two 200 mg pills daily, taken both at once or at separate times during the day. Patients start dosage with a 2-week lead-in period of only 200 mg per day. The lead-in period reduces the likelihood of developing a skin rash, the most common side effect of nevirapine.
The skin rash, which develops in about 20–25 percent of all patients, usually occurs within the first 4 weeks of treatment. It is typically mild to moderate, but can be life threatening. About 25 percent of patients who develop rashes require hospitalization, although less than half of those who are hospitalized must discontinue nevirapine because of it. If a patient develops a skin rash, he or she should contact a physician or other health care professional immediately.
Nevirapine appears to be safe for women who are pregnant. Because the drug passes into breast milk, nevirapine decreases the risk for transmission of HIV from mother to infant.
- Delavirdine (Rescriptor®)
Delavirdine boosts levels of the protease inhibitors in the blood. This is unusual, because the other two non-nucleoside drugs decrease blood levels and possibly the effectiveness of protease inhibitors. Delavirdine increases the levels of indinavir by 300 percent, levels of saquinavir by 200 percent, and levels of nelfinavir by 100 percent. These increases can be helpful in simplifying the dosage of protease inhibitors and overcoming viral resistance.
Rescriptor is approved for use in adults. The FDA-approved dose is 400 mg, three times a day, with or without food. The main side effect of delavirdine is a rash, which occurs in approximately 25% of the patients who take it. The rash is usually treatable and does not require stopping the drug. However, in some cases, the rash is severe and is accompanied by other symtoms (e.g., malaise, fever, muscle or joint pain, blisters, mouth sores, swelling). Patients who experience a serious reaction may need to discontinue taking this drug. Other side effects include headache, nausea, and fatigue.
- Etravirine (Intelence®)
Etravirine was approved by the FDA in January 2008 to treat HIV infections that do not respond to other medications. This drug has not been studied in children under the age of 16 or in women who are pregnant. It is approved for use in adults and is used in combination with other medications.
Side effects of etravirine include nausea and rash. A serious skin reaction may occur in some patients. Long-term effects of this drug are unknown.
Protease inhibitors block an enzyme called HIV protease, which prevents infected cells from producing more HIV. There are 11 U.S. FDA-approved protease inhibitors used to treat HIV. The use of two protease inhibitors in dual protease-inhibitor regimens is popular because of drug interactions that increase potency, reduce dose frequency, require fewer food restrictions, and lower the cost. Long term effects of dual protease-inhibitor regimens are unknown.
Blood levels of protease inhibitors drop significantly shortly after being taken. This makes frequent dosing necessary to maintain a level of the medication in the blood to destroy the virus. Missed doses lead to low blood levels of drug, allowing the virus to multiply, mutate, and develop resistance. Much of the focus of current studies is to develop new medications and new ways of taking medications that maintain proper drug levels, prevent resistance, and overcome the need for frequent dosing.
Protease inhibitors have been associated with new onset diabetes mellitus and may worsen pre-existing diabetes. All patients who are on antiretroviral therapy must be followed closely by a health care professional for treatment-related side effects. PIs can cause elevations in blood levels of sugar, as well as cholesterol and other fats and have been associated with lipodystrophy.
Protease inhibitors approved to treat HIV include the following:
- Saquinavir mesylate (Invirase®, Fortovase®)
Saquinavir was first approved for use in the United States in 1995. It was first known by the brand name Invirase® and is no longer marketed as Fortovase®. The usual dose is six 200 mg pills three times daily or eight 200 mg pills twice daily. This drug is prescribed with ritonavir, which can boost saquinavir levels more than 10 times. Patients usually take 1 ritonavir pill with 2 Invirase pills twice daily.
Side effects include diarrhea, nausea, and upset stomach. Patients may also experience headaches and fatigue.
- Ritonavir (Norvir®)
Ritonavir was the second protease inhibitor approved for use in the United States. Ritonavir has many side effects and interacts with many drugs. The fact that it interacts so readily with other drugs can be used advantageously, if combined with the right drugs. Low doses of ritonavir are now routinely used with saquinavir, indinavir, and amprenavir to boost their levels, increase their potency, and decrease the number of daily doses required. These interactions can also be dangerous leading to unintentional overdoses of prescription medications or illegal drugs.
When taken as the only protease inhibitor, the usual dose is four to six 100 mg pills twice daily. If ritonavir is being used to boost another protease inhibitor, the usual dose is one or two 100 mg pills twice daily.
Ritonavir can cause numbness and tingling of the face and mouth, nausea, diarrhea, belly pain, headaches, and fatigue. Side effects are minimized if the dose of ritonavir is slowly increased over 1 to 2 weeks.
The interaction of ritonavir with other drugs can lead to life-threatening situations. Patients should tell their doctors about all drug use, legal and illegal, to avoid adverse effects resulting from a drug interaction.
- Indinavir (Crixivan®)
Indinavir was approved for use in the United States in 1996. Until recently, the dose of indinavir was two 400 mg pills every eight hours on an empty stomach. If not taken on time or on an empty stomach, blood levels readily drop below what is necessary to kill the virus.
Many HIV specialists now give indinavir along with norvir to overcome this problem. Norvir raises the levels of indinavir in the blood enough to decrease the dosing to every 12 hours instead of every 8. A commonly prescribed dose of indinavir is two 400 mg pills with 100 or 200 mg of norvir twice daily. When taken with norvir, it can be taken with food.
Side effects include kidney stones, belly pain, diarrhea, and dry skin and mouth. Patients who take indinavir should drink plenty of water to prevent or minimize side effects.
- Nelfinavir (Viracept®)
Nelfinavir, which was the fourth protease inhibitor approved for use in the United States, received FDA approval in March 1997. The usual dose is five 250 mg pills or two 625 mg pills twice daily, taken with food.
The main side effect is diarrhea, which occurs in 10–30 percent of patients. This condition is usually treatable and only about 5 percent of patients stop taking nelfinavir because of diarrhea. Other side effects include poor concentration, intermittent headaches, and moderate hypertension (high blood pressure).
- Amprenavir (Agenerase®)
Amprenavir was the fifth protease inhibitor to be approved for HIV treatment. The FDA-approved dose is eight 150 mg pills twice daily. Current studies show that taking ritonavir simultaneously boosts the level of amprenavir. Some HIV specialists now prescribe 100 to 200 mg of ritonavir with three or four 150 mg amprenavir pills twice daily.
The main side effects are skin rash and gastrointestinal complications, including nausea, vomiting, and diarrhea. The skin rash, which usually is mild to moderate but can be life threatening, occurs in more than 25 percent of all patients.
Amprenavir interacts with many other drugs, including antacids, so patients should tell their doctors about all drug use, legal and illegal, to prevent adverse effects resulting from drug interaction.
- Lopinavir and ritonavir (Kaletra®)
Lopinavir and ritonavir, also known as Kaletra, was approved for use by the FDA in September of 2000. Kaletra is a combination of 133 mg of Lopinavir and 33mg of Ritonavir. The usual dose is three pills twice a day. Ritonavir gives Lopinavir levels that are 20-30 times higher than those necessary to kill usual HIV. These high levels of drug may also make Kaletra helpful against resistant HIV.
The most common side effects are diarrhea, nausea and vomiting. Some patients also experience rash, fatigue and headache. Because Kaletra contains ritonavir, it should never be taken with other medications unless the medications have been reviewed by a physician or pharmacist who is an expert in the treatment of HIV. Ritonavir can raise blood levels of many medications to dangerous levels.
- Atazanavir sulfate (ATV, Reyataz®)
This protease inhibitor was approved by the FDA in June 2003. It is approved for use in adults and should be taken with food. Reyataz is taken as a tablet once per day and the dosage depends on whether the patient is just beginning antiretroviral therapy or is changing medications.
Reyataz reacts with a number of other drugs, and patient should notify their doctor of all over-the-counter medications (including herbal remedies) and prescription drugs they are taking before beginning treatment. Side effects include kidney stones, headache, dizziness, nausea, and tingling in the arms and legs. Liver damage may also occur.
- Fosamprenavir calcium (Lexiva®)
Lexiva received FDA approval in October 2003. This drug is used to treat HIV infection in adults and can be taken either once or twice per day.
Common side effects include nausea and vomiting, diarrhea, headache, and skin rash. In some cases, this drug has been shown to worsen diabetes and cause high blood sugar.
- Tipranavir (TPV, Aptivus®)
In 2005, the Food and Drug Administration approved this drug, which must be taken with ritonavir (Norvir®), to treat HIV in adults. It is available as a capsule that must be swallowed and not chewed, and is taken twice per day. Aptivus and Norvir are used in combination with other medications.
Side effects include diarrhea, stomach pain, headache, and fatigue. This drug can also cause liver damage and increase bleeding in patients who have hemophilia.
- Darunavir (Prezista®)
Prezista is a protease inhibitor that was approved in June 2006. It also is taken with Norvir® and is used in combination with other antiretrovirals. Long term effects of this medication are not yet known. It is not approved for use in adults who are just beginning antiretroviral therapy or in children.
Prezista may cause diarrhea, headache, and the common cold. In some cases, it worsens diabetes, results in liver problems, and causes mild-to-severe skin rash.
- Raltegravir (Isentress®)
In October 2007, the FDA approved the HIV integrase strand transfer inhibitor raltegravir (Isentress®) to treat HIV infection. This drug is approved for use in adult patients who are already on antiretroviral therapy. It is used in combination with other medications.
Side effects include nausea, diarrhea, and headache. Raltegravir may increase the risk for serious conditions, such as muscle disorders (myopathy) and the destruction of skeletal muscle (called rhabdomyolysis).
- Dolutegravir (Tivicay)
In August 2013, dolutegravir (Tivicay) was approved to treat HIV-1 infection. According to the FDA, dolutegravir is an integrase strand transfer inhibitor that interferes with one of the enzymes needed for HIV to multiply. This drug is approved for use in adults with HIV who have never taken antiretrovirals, adults who have previously been on antiretroviral therapyincluding other integrase strand transfer inhibitors, and children over the age of 12 who weigh at least 88 pounds who have never taken an integrase strand transfer inhibitor.
Side effects include trouble sleeping and headache. Serious side effects include hypersensitivity and abnormal liver function in patients with hepatitis B or hepatitis C. Patients taking dolutegravir should be monitored for serious side effects.
In December 2012, the FDA approved the first medication to treat diarrhea in people with HIV who are on antiretroviral therapy. This botanical drugcrofelemer (Fulyzaq)is taken twice a day to control diarrhea that is not caused by a viral or bacterial infection, a parasite, or GI condition. Common side effects include upper respiratory infection, cough and elevated levels of the liver enzyme bilirubin.