How Do Protease Inhibitors Work in Antiretroviral Therapy for HIV Infection?

Protease inhibitors are one of the classes of drugs in the combination of drugs used for antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection. Protease inhibitors were first introduced in 1995 and are effective for both HIV-1 and HIV-2 infections.

Nucleoside reverse transcriptase inhibitors (NRTIs) form the backbone of the three-drug ART regimen, and protease inhibitors are often an additional drug class included in the regimen, to improve the chances of controlling the viral growth.

Antiretroviral therapy is a combination treatment regimen for HIV infection, with different classes of drugs that work in different ways. Each ART regimen is tailored to suit individual conditions and requirements. There is no cure for HIV infection, but ART can effectively manage HIV as a chronic disease.

Protease inhibitors have a low incidence of drug resistance in treatment-naive patients (patients undergoing treatment for the first time). Drug resistance tests are performed before ART is initiated, but protease inhibitor-based ART regimens are often started as first-line treatment for acute HIV infection while test results are awaited.

HIV infection is caused by a virus that attacks the human immune system. HIV targets and enters an immune cell known as T-cell, and uses its cell machinery to create more HIV viral copies, which disperse to infect other T-cells.

Uncontrolled HIV infection in its later stages results in acquired immune deficiency syndrome (AIDS), when the immune system becomes highly impaired and loses its ability to fight infections effectively.

Once the HIV enters and integrates its genome with the host cell’s DNA, it makes long chains of HIV proteins. At this stage the virus is immature and noninfectious to other T-cells. The viral DNA then releases an enzyme known as protease, which is essential in breaking up the protein chains to make new functional virus particles.

Protease inhibitors bind to the protease enzyme and inhibit its activity, and prevent the break-up of the protein chains. Formation of new infectious virus particles is then prevented or inhibited.

HIV may eventually mutate and develop resistance to the drugs. Many second-generation protease inhibitors continue to be effective until multiple mutations take place.

Protease inhibitors have a significant potential for interactions with certain drugs and foods. Some of the major side effects of protease inhibitors include the following:

• Gastrointestinal side effects such as
  • Diarrhea
  • Nausea
  • Vomiting
• Metabolic complications such as
  • Dyslipidemia (abnormal level of blood fats)
  • Lipodystrophy (abnormal distribution of fat tissue)
  • Insulin resistance leading to diabetes mellitus
• Kidney or liver damage
• Abnormalities with the heart’s electrical activity

Atazanavir (Reyataz)

Available as capsules and oral powder to be taken with food.

Side effects include:

• Indirect hyperbilirubinemia (high bilirubin levels in blood)
• Prolonged PR interval (abnormal heart rhythm)
• Hyperglycemia (high sugar level in blood)
• Skin rash
• Hyperlipidemia (high level of blood fats)

Darunavir (Prezista)

Available as tablets to be taken with food along with booster drugs such as ritonavir or cobicistat. Approved for antiretroviral treatment-naive patients or treatment-experienced patients without darunavir-resistance mutations.

Side effects include:

• Rash
• Nausea
• Diarrhea
• Hyperlipidemia
• hyperglycemia

Fosamprenavir (Lexiva)

Available as tablets and oral suspension.

Side effects include:

• Rash
• Nausea
• Vomiting
• Diarrhea
• Hyperlipidemia
• Hyperglycemia

Indinavir (Crixivan)

Available as capsules to be taken one hour before two hours after meal, or with skim milk or low-fat meal.

Side effects include:

• Nephrolithiasis (kidney stones)
• Nausea
• Indirect hyperbilirubinemia
• Hyperlipidemia
• Hyperglycemia

Lopinavir/ritonavir (Kaletra)

Available as tablets approved only for antiretroviral treatment–naïve patients or treatment-experienced patients without lopinavir-resistance mutations.

Side effects include:

• Nausea
• Vomiting
• Diarrhea
• Asthenia (abnormal physical weakness)
• Hyperlipidemia
• Hyperglycemia

Nelfinavir (Viracept)

Available as tablets and oral powder to be taken with food.

Side effects include:

• Diarrhea
• Hyperlipidemia
• Hyperglycemia

Ritonavir (Norvir)

Available as tablet, soft gelatin capsule and oral solution, to be taken with food. Used as a boosting drug for other protease inhibitors, or as sole protease inhibitor with gradual increase in dosage.

Side effects include:

• Nausea
• Vomiting
• Diarrhea
• Asthenia
• Hyperlipidemia
• Oral paresthesia (abnormal tingling or burning sensation or numbness in the mouth)
• Hyperglycemia

Saquinavir (Invirase)

Available as tablets and hard gelatin capsule, to be taken along with ritonavir as booster, with food or within two hours after meal.

Side effects include:

• Nausea
• Diarrhea
• Headache
• Hyperlipidemia
• Hyperglycemia
• PR and QT interval prolongation (abnormal heart rhythm)

Tipranavir (Aptivus)

Available as a soft gelatin capsule and oral solution, to be taken with ritonavir as a booster. Approved only for antiretroviral treatment-experienced patients with drug resistance.

Side effects include:

• Hepatotoxicity
• Rash
• Hyperlipidemia
• Hyperglycemia
• Intracranial hemorrhage (rare cases reported)