Indinavir – First-Generation HIV Protease Inhibitor

Merck's Crixivan or indinavir sulphate is a first-generation HIV-protease inhibitor (PI). With AIDS being the leading cause of deaths in the world, PI drugs such as indinavir have demonstrated their ability to significantly improve the health of AIDS patients. They have also helped in increasing the lifespan of people suffering from AIDS.

In November 2009, the generic version of indinavir manufactured by Ranbaxy was included in the World Health Organization's (WHO) pre-qualification list. With the addition of indinavir, Ranbaxy now has 19 antiretrovirals on the overall WHO pre-qualification list.

Inclusion in the list will enable Ranbaxy to provide indinavir at affordable prices to over 70 markets across the world.

Acquired immune deficiency syndrome (AIDS)

Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS) is an ailment that affects the human immune system. The disease is caused by the human immunodeficiency virus (HIV).

The virus progressively affects the immune system and leaves it susceptible to different types of infections and tumours. The disease can be passed on via contact of a mucous membrane. It can also be caused through contact of the bloodstream with bodily fluids such as blood, vaginal fluid, semen and breast milk.

AIDS affects the immune system in such a way that infections triggered by bacteria, viruses and fungi progressively increase. These infections are normally tackled by the immune system but in people suffering from AIDS, the HIV virus damages the immune system.

As a result the immune system is unable to fight against these infections leading to various cancers and tumours. The HIV virus can affect any organ system in the body and lead to conditions such as Kaposi's sarcoma (a cancer), cervical cancer, fevers, night sweats, swollen glands, weakness and weight loss.

Genetic research has shown that HIV originated in west-central Africa in the late 19th or early 20th century. The Centers for Disease Control and Prevention in the US first documented AIDS in 1981. HIV, the cause of the disease was recognised in the early 1980s.

There is no cure for the disease although a few treatments can slow the course of the disease. These treatments include highly active antiretroviral therapy or HAART. This treatment was first introduced in 1996 and has proven to be highly beneficial to many HIV-infected people.

HAART treatments include a combination of at least three types or classes of antiretroviral agents, which aim to reduce complications, infections and HIV viremia below the limit of detection. Although HAART treatment does not cure a patient of AIDS nor does it prevent its return, it has improved the overall health and quality of life in patients.

Indinavir: first-generation HIV-protease inhibitor

Indinavir sulfate is a hydroxyaminopentane amide identified from a string of PIs in the 1990s. Indinavir binds to the active site of the enzyme and inhibits the action of the enzyme.

By doing so the drug stops cleavage of the viral polyproteins, resulting in the creation of immature non-infectious viral particles. The drug has seven active metabolites, one glucuronide conjugate and six oxidative metabolites.

Administration of indinavir reduces a person's risk of contracting any of the secondary illnesses that patients of HIV-AIDS often suffer from and lengthens the time that the HIV virus can be suppressed. Compared to earlier antiretroviral drugs, indinavir is considered to be much more potent.

A combination of the drug with dual nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) set a new standard for treatment of HIV/AIDS. It also laid the foundation for the design and introduction of subsequent antiretroviral drugs.

Clinical trials lead to FDA approval

Indinavir received approval from the US Food and Drug Administration (FDA) on 13 March 1996. It was the eighth antiretroviral approved by the FDA after being studied in more than 2,000 patients. The drug was approved under the FDA's accelerated approval regulations, which were based on 24-week studies.

The studies showed improvements in markers of HIV disease progression including large viral load decreases and CD4 (a glycoprotein) count improvements. The improvements were increased when indinavir was administered in combination with other antiretrovirals.

In Phase I/II trials indinavir was well tolerated although a few side effects were reported. In a Phase III randomised, controlled, clinical end-point study, 1,156 patients were enrolled.

The study showed that the drug in combination with zidovudine and lamivudine significantly slowed the progression of AIDS. Long-term studies are being carried out to test the impact of indinavir in preventing clinical progression of HIV disease.

Marketing commentary

AIDS has now been categorised as a pandemic. In 2007, it was estimated that about 33.2 million people were affected by the disease across the world. It was also estimated that the disease was responsible for the death of 2.1 million people, including 330,000 children.

PIs such as indinavir altered the nature of the AIDS epidemic and transformed it from being a terminal illness to a more manageable one.

Since indinavir is only a first-generation PI, the drug is being increasingly replaced by newer drugs such as lopinavir or atazanavir, which are more convenient to administer and less likely to develop resistance to the virus. Nevertheless, indinavir remains a key antiretroviral drug in the market.