Antiretroviral medications used to treat human immunodeficiency virus (HIV) infection 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 medications are used together to treat HIV infection. These medications 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 medications 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 medications: 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 medications.
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 Medication Action on Life Cycle of HIV
Medications used to treat HIV infection were developed based on the life cycle of HIV. These medications prevent HIV entry into its target cells or inhibit the three enzymes (reverse transcriptase, integrase, and protease) that the virus uses to replicate.
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These medications prevent HIV from replicating in cells and significantly 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 medications, the more quickly their CD4 count is likely to increase and the higher the count is likely to become.
Did You Know...
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HIV invariably develops resistance to any of these medications if they are used alone. Resistance develops after a few days to several months of use, depending on the medication and the virus. HIV becomes resistant to medications because of mutations that occur when it replicates.
Treatment is most effective when two or more medications are given in combination. These combinations of medications are often referred to as combination antiretroviral therapy (cART). cART is used because
Combinations are more powerful than single medications in reducing the amount of HIV in the blood.
Combinations help prevent the development of drug resistance.
cART can increase the CD4 count in people with HIV infection, thus strengthening their immune system and extending their life.
Side effects of antiretroviral medications
Side effects of combinations of antiretroviral medications 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 medications when needed. For most people, doctors can find a combination of medications 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) increases the risk of heart attacks, strokes, and dementia.
Rashes
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 medications differ in their tendency to cause these problems.
Bone density may decrease when cART is used, resulting in osteopenia or osteoporosis. 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 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 medications. 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 affects the brain. Then cART is temporarily interrupted until the infection is controlled.
Interactions with antiretroviral medications
Drug interactions between antiretroviral medications and other medications or between two antiretroviral medications can occur. Thus, people should make sure their doctor knows all the medications they are taking.
Interactions between antiretroviral medications may increase or decrease the effectiveness of the medications.
Also, other substances affect how the body uses some HIV medications. These substances include the following:
Use of antiretroviral medications
Antiretroviral treatment is beneficial only if the medications 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 antiretroviral 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 antiretroviral treatment. However, research has shown that people who are promptly treated with antiretroviral medications 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 medications as directed
Not skipping any doses
Taking the medications for the rest of their life
Taking the medications as directed for a life time is demanding. Some people skip doses or stop taking the medications for a time (called a drug holiday). These practices are dangerous because they enable HIV to develop resistance to the medications.
Because taking HIV medications 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 medications as directed, doctors often prescribe treatment that combines two or more medications in one tablet that can be taken only once a day.
Prevention of opportunistic infections
If the CD4 count is low, medications to prevent opportunistic infections are routinely prescribed, as in the following cases:
Pneumocystis jirovecii pneumonia. This antibiotic also prevents toxoplasmosis, which can damage the brain.
If cryptococcal meningitis, pneumonia, thrush, or a candidal infection in the vagina
Other medications
Other medications may help with the weakness, weight loss, and central obesity that may result from HIV infection:
If men have low testosteronetestosterone levels and lessen symptoms.
If insulin resistance develops, medications to increase sensitivity to insulin may help. If blood levels of cholesterol and triglycerides increase, lipid-lowering medications (statins) can be used to lower them.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Office of AIDS Research: 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
