What Kind of Inhibitor is Lopinavir?
The first case of AIDS (Acquired Immunodeficiency Syndrome) was clinically reported in the early 1980’s in the United States. AIDS is caused by human immunodeficiency virus (HIV) infection. At the time, the disease did not have a name and was not recognized as a specific condition. As increasing numbers of patients reported to clinics with infections and tumors that affect only people who are ‘immunocompromised’, or have a failing immune system, clinicians caught on to the fact that something else was going on. The disease went through several names, before it finally got its current name of AIDS. HIV infections can be symptomless for many years until they start affecting the immune system. At this point, the infected individual will become susceptible to health problems not usually seen in people with an intact immune system. When this progressive weakening of the immune system occurs after being infected with HIV, it leads to AIDS.
Currently, AIDS is still a global epidemic that is concentrated in specific regions in the world. According to the Centers for Disease Control and Prevention (CDC), within the U.S., there are approximately 38,500 new HIV infections and 6,000 AIDS-related deaths in people above the age of 13 every year. While excellent treatment regimens are now available that can help HIV-positive people live normal, healthy lives and prevent the progression of the disease to AIDS, these individuals must remain on medication to treat the condition for the rest of their lives. Treating the infection ensures that the ‘viral load’ will be low, or ideally negligible in the patient meaning that they cannot transmit the virus to uninfected individuals. HIV can only be transmitted through certain body fluids like blood, semen, pre-seminal fluid, vaginal fluids, rectal fluids and breast milk in which the virus must come into contact with other mucus membranes of the body. It is not transmitted by droplet infection through saliva. So, HIV is mainly sexually transmitted but it can also be transmitted through used or shared needles.
Anti-retroviral Therapy (ART) is a very successful type of therapeutic approach developed for patients with an HIV infection. This mode of treatment has been implemented across the globe and has helped in decreasing the amounts of new HIV infections every year according to UNAIDS. HIV is a ‘retrovirus’ that is classified on the basis of its genetic material and has a specific type of life cycle that it adopts to reproduce itself within human cells. Therefore, anti-retroviral therapy refers to a group of therapeutic agents that can target these kinds of viruses by inhibiting certain essential functions that retroviruses need to reproduce themselves within the host (human cells). ARTs are unlikely to be effective against other types of viruses that do not belong to the retrovirus family.
There are several classes of ARTs that inhibit HIV viral reproduction. Drugs within these classes are classified according to which phase of the retrovirus life cycle they inhibit. Usually, a combination of any of these drugs is used together as an ART regimen. The different classes include:
- Entry Inhibitors
- Fusion Inhibitors
- Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
- Non-Nucleoside Reverse Transcriptase Inhibitors
- Integrase Inhibitors
- Protease Inhibitors
One of the most well known ARTs is lopinavir (LPV) which belongs to the class of Protease Inhibitors. What is LPV? Lopinavir is the generic name for the brand, Kaletra, marketed by Abbott Laboratories spinoff, AbbVie. It has been Food and Drug Administration (FDA)-approved to treat or prevent HIV infections since 2000, and is sold as a fixed dose combination with another protease inhibitor, called Ritonavir, in a single pill or solution.
How do Protease Inhibitors work?
In order to understand how HIV protease inhibitors work, let's take a brief look at how the viral life cycle takes place. HIV can complete its life cycle within 1.5 days. This means that the time from entering a human to cell to completion of producing hundreds of new viral particles occurs within this time frame. In order to stop the growth of the virus in the body, drugs are designed that can inhibit any crucial step of the viral life cycle. HIV, like other retroviruses, uses these main steps to reproduce itself after coming into contact with a host.
- First, the virus enters the human cells by binding to specific proteins on the surface of human cells called CD4+ T cells and fusing the viral envelope with the cell’s membrane.
- Once it is inside the cell, the virus converts its genetic material (RNA) into DNA. This DNA can then combine with the human DNA that is inside the nucleus of the cell.
- After it has integrated its DNA with the cell DNA, the viral DNA uses the human host cell to make new proteins necessary for the production of new virions.
- These proteins and viral RNA come together in an ‘assembly’ process at the cell membrane to form ‘immature virions’.
- Finally, these virions must bud away from the cell membrane to produce hundreds of new mature virions that can infect neighboring T-cells by the same process.
The ART drugs within the different classes target a different step of this retroviral life cycle. The protease inhibitors, like lopinavir/ritonavir, inhibit the last step of the viral life cycle to prevent the formation of mature virions. The way they do this is by stopping the activity of the HIV-1 protease enzyme that is necessary to cleave the different protein products in the immature virion in order to form a mature virion. Without this crucial step, the virions remain immature and are not infectious because they cannot spread to other cells due their lack of ability to bud away from the cell membrane.
Lopinavir showed good results in clinical trials in treating HIV by bringing the viral load down in infected individuals. Combining lopinavir, with another HIV protease-1 inhibitor called Ritonavir, increases the ‘bioavailability’ of the drug by slowing down its metabolism in the body once it is taken. Ritonavir alone uses the same mechanism as lopinavir, but it is usually used as a ‘booster’ at a low dose to increase the activity of other ARTs. Lopinavir was one of the first drugs and continues to be one of the few drugs that is only available as a fixed dosage combination with Ritonavir. It is not available in a formulation by itself.
It is important to keep in mind that ARTs cannot cure HIV infections. But they can reduce the amount of active HIV particles in the body to prevent the infection from progressing to AIDS and to keep the infection from being transmitted to others. If taken life-long, many individuals can maintain their well being for a long time.
Anti-retroviral Combination Therapy
How does lopinavir compare with other ARTs that belong to the different classes? Other ART drugs that are not protease inhibitors inhibit different steps of the viral life cycle. The ‘entry inhibitors’ prevent the first step of viral entry into the human cell by targeting different proteins required for that step. The ‘nucleoside reverse transcriptase inhibitors’ and ‘non-nucleoside transcriptase inhibitors’ prevent the conversion of the viral RNA to DNA so that it cannot enter the cell nucleus and start making the proteins necessary to make new virions. The ‘integrase inhibitors’ prevent the joining of converted viral DNA with the human cell-DNA. Currently, drugs from the protease inhibitor class of ARTs are the first-line therapy for individuals diagnosed with HIV infection, highlighting how effective targeting this step of the viral life cycle is. Other ART drugs that belong to the class of HIV protease inhibitors include darunavir, indinavir, nelfinavir, amprenavir and atazanavir. Atazanavir is a first-line therapy protease inhibitor that is safe to be taken during pregnancy.
A standard HIV-treatment regimen includes at least two drugs from different classes. Taking two medications that target different steps of the viral life cycle increases the chances that the viral reproduction process will be halted and new mature viral particles cannot be produced. As long as the virions remain immature, they are not infectious and cannot be transmitted to an uninfected individual. It also decreases the odds of developing resistance to a single drug.
As with any drug, when taking a cocktail of ARTs for HIV treatment, side effects can occur. Always check with your doctor about what to expect if you are prescribed lopinavir or any other medication to treat an HIV infection. More information on lopinavir can be found here.
How to find Lopinavir/Ritonavir at a discount
A prescription is necessary to buy lopinavir. Although the cost of lopinavir has reduced dramatically since its initial approval in 2000, the average current price of lopinavir/ritonavir fixed dose solution is approximately $375 per bottle of 160 ml. This price can vary a bit depending on the pharmacy that you purchase it from. If you choose to purchase the branded from, Kaletra, the cost of purchasing the drug can cost up to double the amount of generic lopinavir/ritonavir. Even with health insurance, this can quickly become a large cost burden since the medication most likely has to be taken life-long to treat HIV. Pharmacy discount cards, like the one available from USA Rx can help you save on the Kaletra or generic lopinavir/ritonavir. The card is free and can simply be presented at your pharmacy the next time you fill your prescription to start saving.