How Effective is antiretroviral Therapy (ART) for HIV?

What is antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection?

ART for HIV is typically a combination of three or more different antiretroviral drugs that each target the human immunodeficiency virus at different points in its replication in the body.

Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection is a treatment regimen used to reduce the amount of the virus in the body (viral load). There is no cure for HIV, but antiretroviral therapy can slow the progress of the infection and reduce the chances of transmission to others.

Many classes of HIV antiretroviral drugs act in different ways to control virus proliferation. Antiretroviral therapy usually is a combination of three or more types of medications that target the virus at different stages of its life cycle. Multiple angles of attack improve the chances of reducing the viral load.

Antiretroviral therapy is started immediately after diagnosis of HIV infection to decrease its risk of progression and transmission. HIV antiretroviral therapy regimen is tailored to suit individual requirements based on several factors that include:

• Other diseases or conditions of the patient 
• Potential interactions with other medications of the patient 
• Patient’s tolerance to ART side effects
• Results of viral drug-resistance tests
• Convenience of the regimen

Antiretroviral therapy is a lifelong treatment, but it can keep HIV-infected people healthy and active for many years. It is important to never stop the medication, even if the viral load drops to undetectable levels. If treatment is interrupted, the virus is more likely to mutate and become drug-resistant.

What is HIV infection?

HIV infection is caused by a virus that attacks the human immune system. Once the HIV enters the bloodstream, it binds to a kind of receptor (CD4) on the surface of the T-cells (also known as CD4 cells). T-cells are a type of white cells (lymphocytes) in the blood that help fight infection. 

The virus enters the T-cell and replicates itself, destroying the host cell. As a result, the body slowly loses its ability to fight infections.

A person contracts an HIV infection by contact with bodily fluids such as blood, semen, vaginal fluids, or breast milk from an infected person. Primary modes of HIV transmission are:

• Sexual contact
• Sharing needles for injecting drugs
• From mother to the baby during pregnancy, delivery, or breastfeeding

Acquired immune deficiency syndrome (AIDS) occurs in the later stages of an HIV infection. When HIV infection progresses to an extent that a person’s immune system becomes too weak to fight off common infections, the person becomes susceptible to certain cancers and tuberculosis.

There are two main types of human immunodeficiency virus, HIV-1 and HIV-2, and each type has multiple groups and strains of virus. Both HIV infections can lead to AIDS, but they are different from each other.  HIV-1 is the most common infection found worldwide and referred to as HIV. HIV-2 is found mostly in a small population in West Africa, and in a few people in the US primarily from West Africa.

What is HIV?
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How effective is ART for HIV infection?

Antiretroviral therapy has become significantly advanced with the development of new drugs and drug combinations. With the advent of highly active antiretroviral therapy (HAART), HIV-1 is now manageable as a chronic disease. Along with ART, adopting safe and healthy lifestyle habits is essential for effective management of HIV infection.

Though HIV infection cannot be completely eliminated, antiretroviral therapy can

• Control the progression of the infection
• Improve the immune system’s function
• Reduce HIV infection-related diseases and improve longevity and quality of life
• Prevent HIV transmission

How does antiretroviral therapy for HIV infection work?

Antiretroviral therapy works by preventing viral replication in the body. This allows the body’s immune system to recover. ART is a combination of drugs that act on the virus in different ways at different stages in its life cycle.

Unlike bacteria, viruses cannot multiply on their own. Viruses use the host cell’s genetic machinery to make copies of themselves. Viruses are tiny microbes consisting of just a bit of genetic material (DNA or RNA) covered with an envelope (capsid) and a protein with a sugar (glycoprotein) on the surface. 

The human immunodeficiency virus is a type of RNA virus known as a retrovirus, named for a special enzyme known as reverse transcriptase. The HIV uses this enzyme to convert its RNA into DNA to fuse with the nucleus of the immune cells. The life cycle of the HIV is as follows:

• Binding: The HIV uses the glycoprotein to attach itself to the CD4 receptor on the T-cell’s surface.
• Fusion: The HIV fuses its capsid with the cell membrane and enters the T-cell.
• Reverse transcription: The HIV converts the RNA into complementary DNA (cDNA) using the reverse transcriptase enzyme, which allows it to enter the host cell’s nucleus.
• Integration: The HIV cDNA releases an enzyme known as integrase to insert itself into the T-cell’s DNA chain.
• Replication: The infected DNA makes long chains of HIV proteins which are building blocks for more HIV particles (virions).
• Assembly: The new HIV proteins and HIV RNA move to the T-cell’s surface and assemble into immature (noninfectious) HIV, while the host cell is destroyed.
• Budding: The new HIV virus that comes out of the destroyed T-cell, releases an enzyme known as protease. This enzyme breaks up the long protein chains and creates mature (infectious) viruses with a capsid and a core RNA, which disperse to infect more T-cells.

The above stages are essential for the HIV to multiply. Each drug in the antiretroviral therapy combination disrupts the HIV’s life cycle at a different stage inhibiting its growth. The HIV may mutate and develop drug resistance, in which case alternate drug combinations will be necessary.

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What are the different types of ART for HIV infection?

Antiretroviral therapy drugs are primarily divided into the following classes:

• Nucleoside reverse transcriptase inhibitors (NRTIs): Work at the reverse transcription stage by incorporation into the viral cDNA, and stop the DNA formation.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Work at the reverse transcription stage by inhibiting the release of reverse transcriptase enzyme.
• Protease inhibitors (PIs): Work at the budding stage by binding to the viral protease enzyme and prevent the maturation of the budded virus into infectious virions.
• Integrase inhibitors (INSTIs): Work at the integration stage by blocking the integrase enzyme, without which the HIV cDNA cannot insert itself into the CD4 DNA chain.
• Fusion inhibitors (FIs): Work by preventing the HIV’s fusion and entry into the CD4 or any other immune cell.
• Chemokine receptor antagonists (CCR5 antagonists): CCR5 antagonists are also fusion inhibitors which prevent certain strains of virus that enter through the CCR5 receptor, which is another receptor on the T-cell surface.
• Post-attachment entry inhibitors: These do not prevent the virus from binding to the CD4 receptor, but block further interaction and entry into the T-cell.
• Pharmacokinetic enhancers: These are drugs which enhance the performance of ART drugs by delaying their breakdown and making them remain for a longer duration in the body.
• Complete regimen combination ARTs: Antiretroviral therapy is also available in fixed dose, single pill combinations as a complete regimen for people who have difficulty taking several pills.

ART is generally initiated with two NRTIs and a drug from NNRTI, PI or INSTI class. The combination of drugs may be changed if the patient develops resistance to any of the drugs or is unable to tolerate side effects.

What are the DHHS guidelines for administration of ART?

An estimated 36.7 million people are infected with HIV worldwide, and 1.1 million in the United States. The US has about 40,000 new infections occurring each year. The US Department of Health and Human Services panel has issued guidelines to tackle the disease, based on results of clinical trials and expert opinions, which are updated on an ongoing basis.

The guidelines recommend the dosages and combination of drugs for different groups of patients such as:

Treatment-naive patients (patients who are treated for the first time)

• Treatment-experienced patients
• Regimen change for any reason
• Special groups that include the following:
  • Pregnancy
  • Postexposure prophylaxis (preventive)
  • Preexposure prophylaxis
  • Adolescents
  • Patients with acute HIV infection
  • HIV discordant couples (only one among the couple has HIV)
  • Patients with coinfections such as
    • Tuberculosis
    • Hepatitis B
    • Hepatitis C