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Drug Treatment of Human Immunodeficiency Virus (HIV) Infection

By

Edward R. Cachay

, MD, MAS, University of California, San Diego

Last full review/revision Apr 2021| Content last modified Apr 2021
Click here for the Professional Version
Topic Resources

Antiretroviral drugs 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 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.

  • 1. HIV first attaches to and penetrates its target cell. The overall classes of drugs that act against HIV at this stage are called entry inhibitors, and they included attachment inhibitors, post-attachment inhibitors, and fusion inhibitors.

  • 2. HIV releases RNA, the genetic code of the virus, into the cell. For the virus to replicate, its RNA must be converted to DNA. Drugs called reverse transcriptase inhibitors can prevent HIV reverse transcriptase from converting HIV RNA into DNA.

  • 3. The viral DNA enters the cell’s nucleus.

  • 4. With the help of an enzyme called integrase (also produced by HIV), the viral DNA becomes integrated with the cell’s DNA. At this stage, drugs called integrase inhibitors can prevent HIV DNA from being integrated into human DNA.

  • 5. The DNA of the infected cell now produces viral RNA as well as proteins that are needed to assemble a new HIV.

  • 6. A new virus is assembled from RNA and short pieces of protein.

  • 7. The virus pushes (buds) through the membrane of the cell, wrapping itself in a fragment of the cell membrane and pinching off from the infected cell.

  • 7.5 and 8. To be able to infect other cells, the budded virus must mature. Another HIV enzyme (HIV protease) is crucial to this maturation. At this stage, drugs called protease inhibitors can prevent the maturation of the HIV virus.

Sites of Drug Action on Life Cycle of HIV

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...

  • Drugs used to treat HIV infection help only if people take the drugs consistently. Missing doses enables the virus to replicate and develop resistance.

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) 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. 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 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 affects the brain. Then cART is temporarily interrupted until the infection is controlled.

Interactions with antiretroviral drugs

Drug interactions 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 (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.

Table
icon

Drugs for HIV Infection

Drug*

Some Side Effects†

Attachment inhibitor

Fostemsavir

Nausea and vomiting

Possible elevations in liver enzymes in patients with hepatitis B or C virus

Entry (fusion) inhibitors

Enfuvirtide (T-20)

Painful rash at the injection site and allergic (hypersensitivity) reactions (including rash, fever, chills, nausea, and low blood pressure), numbness and tingling in the hands and feet (peripheral neuropathy), insomnia, and loss of appetite

Increased risk of pneumonia

Maraviroc (a CCR-5 inhibitor)

Inadequate blood flow (ischemia) to the heart or heart attacks

Post-attachment inhibitors

Ibalizumab

Diarrhea, tiredness, and dizziness

Integrase inhibitors

Bictegravir

Allergic (hypersensitivity) reactions including rash (which is occasionally severe or life threatening), headache, insomnia, and muscle aches

Dolutegravir

Possible increased risk of fetal neural tube defects if used during early pregnancy

Elvitegravir

Nausea and diarrhea

Raltegravir

Allergic (hypersensitivity) reactions including rash (which is occasionally severe or life threatening) and muscle aches

Non-nucleoside reverse transcriptase inhibitors

All of these drugs

Rash (occasionally severe or life threatening) and liver dysfunction

Doravirine

Fatigue, headache, dizziness, and rarely insomnia

Efavirenz

Dizziness, sleepiness, nightmares, confusion, agitation, forgetfulness, and intense feelings of well-being (euphoria)

Etravirine

Severe or life-threatening rashes

Nevirapine

Severe or life-threatening liver dysfunction and rashes, especially during the first 18 weeks of treatment

Rilpivirine

Depression, headache, and insomnia, but fewer side effects involving brain function than efavirenz

Nucleoside reverse transcriptase inhibitors

All of these drugs

Lactic acidosis (buildup of lactic acid, a waste product of metabolism), which can be life threatening, and liver damage

Abacavir (ABC)

A severe, sometimes fatal allergic reaction with fever, rash, nausea, vomiting, difficulty breathing, a sore throat, and/or cough

Loss of appetite, nausea, and vomiting

Emtricitabine (FTC)

Headache, nausea, diarrhea, and darkening of the skin (hyperpigmentation), especially on the palms and soles

Lamivudine (3TC)

Headache, fatigue, and peripheral nerve damage

Rarely, pancreas inflammation (pancreatitis)

Zidovudine (AZT or ZDV)

Anemia, susceptibility to infection (resulting from bone marrow damage), liver damage, weakness, and muscle aches

Rarely, pancreas inflammation

Nucleotide reverse transcriptase inhibitors

Tenofovir alafenamide fumarate (TAF)

Fewer side effects involving the kidneys and bone density than tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate (TDF)

Kidney injury

Decreased bone density

Diarrhea, nausea, vomiting, and headache

Protease inhibitors‡

All of these drugs

Nausea, vomiting, diarrhea, abdominal discomfort, increased levels of blood sugar and cholesterol (common), increased abdominal fat, liver dysfunction, and a bleeding tendency (particularly in people with hemophilia)

Atazanavir (ATV)

Rash and yellowing of the skin and whites of the eyes (jaundice)

Darunavir

Liver injury

Headache, diarrhea, severe rash, fever, and allergic reactions

Fosamprenavir

Rash

Lopinavir (LPV)

Mouth tingling and altered taste

Nelfinavir (NLF)

Diarrhea

Tipranavir (TPV)

Possibly life-threatening liver inflammation and bleeding within the brain

*All drugs, except enfuvirtide, are taken by mouth. Enfuvirtide is injected under the skin.

† Side effects listed for the class of drug can occur when any drug in that class is used.

‡ All protease inhibitors are used with a booster of either low dose ritonavir or cobicistat.

Prevention of opportunistic infections

If the CD4 count is low, drugs to prevent opportunistic infections are routinely prescribed, as in the following cases:

Other drugs

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 (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.

NOTE: This is the Consumer Version. DOCTORS: Click here for the Professional Version
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