Antiretroviral Treatment of Human Immunodeficiency Virus (HIV) Infection

Classes of antiretroviral medications

Several classes of antiretroviral medications are used together in ART to treat HIV infection. These medications block HIV from entering human cells or block the activity of 1 of the 3 enzymes HIV needs to reproduce (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 the HIV enzyme called reverse transcriptase from converting HIV RNA into DNA. There are 3 types of these medications: nucleoside, nucleotide, and non-nucleoside.

• Protease inhibitors prevent the HIV enzyme called protease from activating certain proteins inside newly produced viruses. The result is immature, defective virus that does not yet cause HIV infection.

• Entry inhibitors, sometimes called fusion inhibitors, prevent HIV from entering cells. To enter a cell, HIV must bind to a CD4 receptor and 1 other receptor, such as the CCR-5 receptor. CCR-5 inhibitors block the CCR-5 receptor, preventing HIV from entering cells.

• Post-attachment inhibitors also prevent HIV from entering cells but in a different way than entry inhibitors do. Post-attachment inhibitors are used mainly for people who have HIV infection that is resistant to several other medications.

• Integrase inhibitors prevent HIV DNA from being integrated into the cell's DNA by blocking the HIV enzyme called integrase.

• Attachment inhibitors prevent HIV from attaching to and entering T cells and other immune cells.

• Capsid inhibitors interfere with the outer shell (capsid) of HIV.

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 from entering T cells or inhibit 1 of the 3 enzymes (reverse transcriptase, integrase, and protease) that the virus uses to replicate (reproduce) or to attach to and enter cells. 1. HIV first attaches to and enters its target cell. The classes of antiretroviral medications that act against HIV at this stage are entry (fusion) inhibitors, attachment inhibitors, post-attachment inhibitors, and capsid inhibitors. 1.5. After entering the cell, the outer shell (capsid) of HIV undergoes uncoating and is transported within the cell. At this stage, the class of medications that acts against HIV is capsid inhibitors. These medications interfere with capsid function and prevent viral replication. 2. HIV releases RNA, the genetic code of the virus, into the cell. For the virus to replicate, its RNA must be converted into DNA. At this stage, the class of medications that acts against HIV is reverse transcriptase inhibitors. These medications prevent the HIV enzyme called reverse transcriptase from converting HIV RNA into DNA. 3. The HIV DNA enters the cell’s nucleus. Capsid inhibitors can prevent this from happening. 4. With the help of an enzyme produced by HIV called integrase, the HIV DNA becomes integrated into the cell’s DNA. At this stage, the class of medications that acts against HIV is integrase inhibitors. These medications prevent HIV DNA from being integrated into human DNA. 5. The DNA of the infected cell now produces HIV RNA and proteins needed to assemble a new virus. 6. A new virus is assembled from RNA and short pieces of protein. Capsid inhibitors can interfere with proper assembly of the virus. 7. The immature virus pushes (buds) through the cell membrane, wrapping itself in a fragment of the cell membrane before pinching off from the infected cell. At this stage, the immature virus can not yet infect other cells. 7.5 and 8. To be able to infect other cells, the budded virus must mature. It becomes mature when another enzyme produced by HIV called protease breaks up structural proteins in the immature virus, causing them to rearrange. At this stage, the class of medications that acts against HIV is protease inhibitors. These medications prevent the maturation of HIV.

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 infection can be reversed. Doctors can detect this reversal by measuring the CD4 count, which begins to return toward a normal level over weeks to months. With ART, 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 ART, the more quickly their CD4 count is likely to increase and the higher the count is likely to become. ART also causes the amount of circulating virus in the blood (viral load) to decrease.

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 2 or more medications are given in combination. These combinations of medications are often referred to as combination ART (cART). cART is used because:

• Combinations of medications are more powerful than single medications in reducing the amount of HIV in the blood.

• Combinations help prevent the development of resistance.

• Some HIV medications (such as ritonavir) boost the blood levels of other HIV medications (including most protease inhibitors) by slowing their removal from the body and thus increasing their effectiveness.

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 cART 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 some side effects before they cause symptoms and enable doctors to change ART when needed. For most people, doctors can create an ART regimen that causes minimal side effects.

Metabolism of fats may be disturbed, probably primarily by protease inhibitors. The following may result:

• Fat is redistributed and accumulates in the trunk, neck, abdomen, and breasts. This side effect is called lipodystrophy. Fat is lost from the face, arms, and legs. This side effect is called lipoatrophy.

• The body becomes less sensitive to the effects of insulin (called insulin resistance).

• Blood levels of cholesterol and triglycerides (2 types of fat in the blood) and glucose are increased.

Lipodystrophy and Lipoatrophy in HIV Infection

Image

The medications used to treat HIV infection can cause side effects.

The left photo shows the accumulation of fat (lipodystrophy) in the neck known as “buffalo hump” (red arrow). The right photo shows increased abdominal fat.

The right photo also shows the loss of fat in the arms and legs (lipoatrophy).

Edward R. Cachay, MD, MAS

People who have excess abdominal fat, high blood pressure (which may be caused by HIV itself or some types of ART), insulin resistance or diabetes, and abnormal levels of cholesterol and other fats in the blood (dyslipidemia) have a disorder called metabolic syndrome. Metabolic syndrome increases the risk of heart attack, stroke, and dementia.

Rashes (skin reactions) are a side effect of many medications. Some skin reactions in people taking ART can be very dangerous, especially if the medication causing the reaction is 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), and liver damage that occasionally progresses to severe liver 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.

High blood pressure may be caused by HIV infection and some antiretroviral medications, making regular monitoring and management of cardiovascular risk factors important.

Immune reconstitution inflammatory syndrome (IRIS)

People with HIV infection who start ART may at first worsen because of IRIS. In IRIS, ART activates the weakened immune system so that it can respond to any of the opportunistic infections that linger in the body, some of which may have previously been successfully treated. Thus, as the immune system begins to recover (reconstitute) with ART, the resulting strong inflammatory response can worsen or unmask symptoms of an underlying opportunistic infection, and the symptoms vary depending on which specific infection is present.

There are 2 forms of IRIS:

• Paradoxical IRIS: Worsening of symptoms of an infection that doctors have already diagnosed

• Unmasked IRIS: 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, steroids (also called corticosteroids or glucocorticoids) are given for a short time and are often effective. Paradoxical IRIS is more likely to be severe when ART is started soon after treatment of an opportunistic infection is started. Thus, for some opportunistic infections, ART 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, steroids are also used. Usually, when unmasked IRIS occurs, ART is continued. An exception is when a cryptococcal infection affects the brain. Then ART is temporarily interrupted until the infection is controlled.

Interactions with antiretroviral medications

Drug interactions between antiretroviral medications and other medications or between 2 or more 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.

St. John's wort (a medicinal herb) should not be used because it causes the body to process protease inhibitors and non-nucleoside reverse transcriptase inhibitors more quickly and thus makes them less effective.

Use of antiretroviral medications

ART is beneficial only if the medications are taken on schedule. Missing doses allows the virus to replicate and develop resistance.

Treatment does not eliminate the virus from the body, but treatment does decrease the level of HIV in the blood so much that in some people it cannot be detected in blood or other fluids or tissues. An undetectable level of HIV is the goal of treatment (U=U). If treatment is stopped, the HIV level increases, and the CD4 count begins to fall.

ART should be started as soon as possible, even if people are not sick and their CD4 count is still above 500 cells per microliter of blood (most healthy adolescents and adults have a CD4 count of about 500 to 1,200 cells per microliter of blood ). Doctors used to wait until the CD4 count was below 500 to start ART. However, research has shown that people who are promptly treated with ART are less likely to develop and die of advanced HIV-related complications.

Before starting a treatment regimen, people are taught about the necessity of the following:

• Taking ART as directed

• Not skipping any doses

• Taking ART for the rest of their life

Taking ART as directed for life is demanding. Some people skip doses or stop taking the medications for a time. These practices are not recommended because they enable HIV to develop resistance to the medications.

Because taking ART irregularly often leads to drug resistance, health care professionals make sure that people are both willing and able to adhere to the treatment regimen. To simplify the medication schedule and to help people take ART as directed, health care professionals often prescribe treatment that combines 2 or more medications in 1 tablet that needs to be taken only once a day.

Doctors may stop treatment temporarily if people develop another disorder or infection that requires treatment or if side effects are severe and doctors must determine which medication is causing them. Stopping treatment is usually safe if all medications are stopped at the same time. Medications are restarted once the dose of the medication causing side effects has been modified or another medication is substituted for it and doctors determine that it is safe to restart treatment. An exception is abacavir. People who develop a fever or rash when taking abacavir should stop taking it and not take it again because they may have a severe, potentially fatal reaction to it.

Prevention of opportunistic infections

If the CD4 count is low, medications 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 sulfamethoxazole/trimethoprim is given to prevent Pneumocystis jirovecii pneumonia. This antibiotic also prevents toxoplasmosis, which can damage the brain.

• If the CD4 count drops below 50 cells per microliter of blood and the person is not receiving ART or still has the virus in their blood while taking ART, the antibiotic azithromycin or clarithromycin is given to prevent Mycobacterium avium complex infection. If people cannot take either of these medications, they are given another antibiotic called rifabutin.

• If a fungal infection such as cryptococcal meningitis, pneumonia, thrush, candidal infection of the esophagus, or a candidal infection in the vagina recurs, people may be given the antifungal medication fluconazole.

• If herpes simplex infections of the mouth, lips, genitals, or rectum recur, people may require prolonged treatment with the antiviral medication acyclovir.

If a person with HIV infection has signs of inactive (latent) tuberculosis (TB) (usually diagnosed with a positive skin test or a specific blood test), is at high risk of exposure to TB, or has lived in an area where TB is common, doctors recommend preventive medications to stop TB from becoming active.

Other medications

Other medications may help with the weakness, weight loss, and excess abdominal fat that may result from ART:

• 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 medication that releases growth hormone) reduce excess abdominal fat.

If insulin resistance develops, medications to increase sensitivity to insulin such as metformin may help. If blood levels of cholesterol and triglycerides increase, lipid-lowering medications (statins) can be used to lower them.