Antiretroviral drugs used to treat human immunodeficiency virus (HIV) infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection is a viral infection that progressively destroys certain white blood cells and can cause acquired immunodeficiency syndrome (AIDS). HIV is transmitted... read more aim to do the following:
Reduce the amount of HIV RNA (viral load) in the blood to an undetectable amount
Restore the CD4 count to a normal level
Several classes of antiretroviral drugs are used together to treat HIV infection. These drugs block HIV from entering human cells or block the activity of one of the enzymes HIV needs to replicate inside human cells and/or integrate its genetic material into human DNA.
The drugs are grouped into classes based on how they act against HIV:
Reverse transcriptase inhibitors prevent HIV reverse transcriptase from converting HIV RNA into DNA. There are three types of these drugs: nucleoside, nucleotide, and non-nucleoside.
Protease inhibitors prevent protease from activating certain proteins inside newly produced viruses. The result is immature, defective HIV that does not infect new cells.
Entry (fusion) inhibitors prevent HIV from entering cells. To enter a human cell, HIV must bind to a CD4 receptor and one other receptor, such as the CCR-5 receptor. One type of entry inhibitor, CCR-5 inhibitors, blocks the CCR-5 receptor, preventing HIV from entering human cells.
Post-attachment inhibitors also prevent HIV from entering cells but in a different way from fusion inhibitors. These are used mainly for HIV infection that is resistant to several other drugs.
Integrase inhibitors prevent HIV DNA from being integrated into human DNA.
Attachment inhibitors prevent HIV from attaching to host T cells and other immune cells; thus they are unable to enter those cells.
Sites of Drug Action on Life Cycle of HIV
Drugs used to treat HIV infection were developed based on the life cycle of HIV. These drugs prevent HIV entry into its target cells or inhibit the three enzymes (reverse transcriptase, integrase, and protease) that the virus uses to replicate.
These drugs prevent HIV from replicating in cells and dramatically reduce the amount of HIV in the blood over a few days to weeks. If replication is sufficiently slowed, the destruction of CD4+ lymphocytes by HIV is decreased and the CD4 count begins to increase. As a result, much of the damage to the immune system caused by HIV can be reversed. Doctors can detect this reversal by measuring the CD4 count, which begins to return toward normal levels over weeks to months. The CD4 count continues to increase for several years but at a slower rate.
Early diagnosis of HIV infection is important because it enables doctors to identify people with HIV infection before their CD4 cell count decreases too much. The sooner people start taking antiretroviral drugs, the more quickly their CD4 count is likely to increase and the higher the count is likely to become.
Did You Know...
HIV invariably develops resistance to any of these drugs if they are used alone. Resistance develops after a few days to several months of use, depending on the drug and the virus. HIV becomes resistant to drugs because of mutations that occur when it replicates.
Treatment is most effective when two or more drugs are given in combination. These combinations of drugs are often referred to as combination antiretroviral therapy (cART). cART is used because
Combinations are more powerful than single drugs in reducing the amount of HIV in the blood.
Combinations help prevent the development of drug resistance.
Some HIV drugs (such as ritonavir) boost the blood levels of other HIV drugs (including most protease inhibitors) by slowing their removal from the body and thus increase their effectiveness.
cART can increase the CD4 count in HIV-infected people, thus strengthening their immune system and extending their life.
Side effects of antiretroviral drugs
Side effects of combinations of antiretroviral drugs may be unpleasant and serious. However, doctors can prevent many serious problems (such as anemia, hepatitis, kidney problems, and pancreatitis) by regularly examining the person and doing blood tests. The blood tests can detect side effects before they become serious and enable doctors to change antiretroviral drugs when needed. For most people, doctors can find a combination of drugs with minimal side effects.
Metabolism of fats may be disturbed, probably primarily by protease inhibitors. The following may result:
Fat accumulates in the abdomen and breasts of women (called central obesity), and it is lost from the face, arms, and legs.
The body become less sensitive to insulin's effects (called insulin resistance)
Blood levels of cholesterol and triglycerides (two types of fat in the blood) are increased.
This combination of problems (called metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal fat), high blood pressure, resistance to the effects of insulin (insulin resistance) or diabetes,... read more ) increases the risk of heart attacks, strokes, and dementia.
Rashes (skin reactions) are a side effect of many drugs. Some skin reactions can be very dangerous, especially if the drug causing the reaction is nevirapine or abacavir.
Mitochondria (structures within cells that generate energy) can be damaged when certain nucleoside reverse transcriptase inhibitors are used. Side effects include anemia, foot pain caused by nerve damage (neuropathy), liver damage that occasionally progresses to severe liver failure, and heart damage that can result in heart failure. Individual drugs differ in their tendency to cause these problems.
Bone density may decrease when cART is used, resulting in osteopenia or osteoporosis Osteoporosis Osteoporosis is a condition in which a decrease in the density of bones weakens the bones, making breaks (fractures) likely. Aging, estrogen deficiency, low vitamin D or calcium intake, and... read more . Most people with these disorders do not have any symptoms, but they are at higher risk of fracturing a bone.
Immune reconstitution inflammatory syndrome
The immune reconstitution inflammatory syndrome (IRIS) sometimes occurs when cART is successful.
In IRIS, symptoms of various infections worsen or appear for the first time because immune responses improve (are reconstituted), increasing inflammation Inflammation Natural barriers and the immune system defend the body against organisms that can cause infection. (See also Lines of Defense.) Natural barriers include the skin, mucous membranes, tears, earwax... read more at sites of infection. Symptoms sometimes worsen because parts of dead viruses persist, triggering immune responses.
There are two forms of this syndrome:
Paradoxical IRIS, which refers to the worsening of symptoms of an infection that doctors have already diagnosed
Unmasked IRIS, which refers to the first appearance of symptoms of an infection that doctors had not previously diagnosed
Paradoxical IRIS typically occurs during the first few months of treatment and usually resolves on its own. If it does not, corticosteroids, given for a short time, are often effective. Paradoxical IRIS is more likely to be severe when cART is started soon after treatment of an opportunistic infection is started. Thus, for some (but not all) opportunistic infections, cART is delayed until treatment of the opportunistic infection has reduced or eliminated the infection.
In people with unmasked IRIS, doctors treat the newly identified opportunistic infection with antimicrobial drugs. Occasionally, when the symptoms are severe, corticosteroids are also used. Usually, when unmasked IRIS occurs, cART is continued. An exception is when a cryptococcal infection Cryptococcosis Cryptococcosis is an infection caused by the fungus Cryptococcus neoformans or Cryptococcus gattii. People may have no symptoms or may have headache and confusion, a cough and... read more affects the brain. Then cART is temporarily interrupted until the infection is controlled.
Interactions with antiretroviral drugs
Drug interactions Drug Interactions The effect a drug has on a person may be different than expected because that drug interacts with Another drug the person is taking (drug-drug interaction) Food, beverages, or supplements the... read more between antiretroviral drugs and other drugs or between two antiretroviral drugs can occur. Thus, people should make sure their doctor knows all the drugs they are taking.
Interactions between antiretroviral drugs may increase or decrease the effectiveness of the drugs.
Also, other substances affect how the body uses some HIV drugs. These substances include the following:
Grapefruit juice increases the levels of saquinavir, increasing the risk of side effects.
St. John's wort St. John’s Wort The reddish substance in the flowers of St. John’s wort contains numerous biologically active compounds, including hypericin and hyperforin. (See also Overview of Dietary Supplements.) People... read more (a medicinal herb) causes the body to process protease inhibitors and non-nucleoside reverse transcriptase inhibitors more quickly and thus makes them less effective.
Use of antiretroviral drugs
Antiretroviral treatment is beneficial only if the drugs are taken on schedule. Missing doses allows the virus to replicate and develop resistance.
Treatment cannot eliminate the virus from the body, although the HIV level often decreases so much that it cannot be detected in blood or other fluids or tissues. An undetectable level is the goal of treatment. If treatment is stopped, the HIV level increases, and the CD4 count begins to fall.
The best time to start drug treatment is as soon as possible, even if people are not sick and their CD4 count is still above 500 (normal is 500 to 1,000). Doctors used to wait until the CD4 count was below 500 to start drug treatment. However, research has shown that people who are promptly treated with antiretroviral drugs are less likely to develop AIDS-related complications and to die of them.
Before starting a treatment regimen, people are taught about the necessity of the following:
Taking drugs as directed
Not skipping any doses
Taking the drugs for the rest of their life
Taking the drugs as directed for a life time is demanding. Some people skip doses or stop taking the drugs for a time (called a drug holiday). These practices are dangerous because they enable HIV to develop resistance to the drugs.
Because taking HIV drugs irregularly often leads to drug resistance, health care practitioners try to make sure that people are both willing and able to adhere to the treatment regimen. To simplify the drug schedule and to help people take the drugs as directed, doctors often prescribe treatment that combines two or more drugs in one tablet that can be taken only once a day.
Doctors may stop treatment temporarily if people develop another disorder that requires treatment or if side effects are severe and doctors must determine which drug is causing them. Stopping treatment is usually safe if all drugs are stopped at the same time. Drugs are restarted once the dose of the drug causing problems has been modified or another drug is substituted for it and doctors determine that it is safe to restart treatment. An exception is abacavir. If people have had a fever or rash when they were taking abacavir, the drug should be permanently stopped. Such people may have a severe, potentially fatal reaction to abacavir if they take it again.
Prevention of opportunistic infections
If the CD4 count is low, drugs to prevent opportunistic infections are routinely prescribed, as in the following cases:
If the CD4 count drops below 200 cells per microliter of blood, the antibiotic trimethoprim-sulfamethoxazole is given to prevent Pneumocystis jirovecii pneumonia Causes . This antibiotic also prevents toxoplasmosis Toxoplasmosis Toxoplasmosis is infection caused by the single-celled protozoan parasite Toxoplasma gondii. Infection occurs when people unknowingly ingest toxoplasma cysts from cat feces or eat contaminated... read more , which can damage the brain.
If the CD4 count drops below 50 cells per microliter of blood, azithromycin taken weekly or clarithromycin taken daily may prevent Mycobacterium avium complex infections Infections Caused by Bacteria Related to Tuberculosis (TB) The bacteria that cause tuberculosis (TB) are classified as mycobacteria. Many types of mycobacteria exist. Many of the types that do not cause tuberculosis (called nontuberculous mycobacteria)... read more . If people cannot take either of these drugs, they are given rifabutin.
If cryptococcal meningitis Cryptococcosis Cryptococcosis is an infection caused by the fungus Cryptococcus neoformans or Cryptococcus gattii. People may have no symptoms or may have headache and confusion, a cough and... read more , pneumonia Overview of Pneumonia Pneumonia is an infection of the small air sacs of the lungs (alveoli) and the tissues around them. Pneumonia is one of the most common causes of death worldwide. Often, pneumonia is the final... read more , thrush Symptoms , or a candidal infection in the vagina Vaginal Yeast Infection (Candidiasis) The vagina is infected by a yeast called Candida, usually Candida albicans, resulting in a yeast infection called candidiasis. Being pregnant or having diabetes or a weakened immune... read more recurs, people may be given the antifungal drug fluconazole for a long time.
If herpes simplex infections Herpes Simplex Virus (HSV) Infections Herpes simplex virus infection causes recurring episodes of small, painful, fluid-filled blisters on the skin, mouth, lips (cold sores), eyes, or genitals. This very contagious viral infection... read more of the mouth, lips, genitals, or rectum recur, people may require prolonged treatment with an antiviral drug (such as acyclovir).
Other drugs may help with the weakness, weight loss, and central obesity that may result from HIV infection:
Megestrol and dronabinol (a marijuana derivative) stimulate appetite. Many people find that natural marijuana is even more effective, and its use for this purpose has been legalized in a few states.
If men have low testosterone levels plus fatigue, anemia, and/or muscle loss, they may be given testosterone by injection or through patches placed on the skin. Testosterone treatments can increase testosterone levels and lessen symptoms.
Growth hormone and tesamorelin (an injectable drug that releases growth hormone) reduce the central obesity that may result from HIV and its treatment.
If insulin resistance develops, drugs to increase sensitivity to insulin may help. If blood levels of cholesterol and triglycerides increase, lipid-lowering drugs Lipid-lowering drugs Dyslipidemia is a high level of lipids (cholesterol, triglycerides, or both) or a low high-density lipoprotein (HDL) cholesterol level. Lifestyle, genetics, disorders (such as low thyroid hormone... read more (statins) can be used to lower them.
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
HIVinfo: Information from the National Institutes of Health (NIH), including a glossary of HIV-related terms and a drug database
The American Foundation for AIDS Research: Resources regarding the support of AIDS research, HIV prevention, treatment education, and advocacy
Centers for Disease Control and Prevention (CDC): HIV Treatment as Prevention: Information for patients about antiretroviral therapy used to reduce the amount of HIV in the body to keep the immune system working and prevent illness