lopinavir and ritonavir (Kaletra): Potential COVID-19 Drug

Kaletra is an oral medication that is a combination of lopinavir and ritonavir. It is used for treating infections with the human immunodeficiency virus (HIV). It is in a class of drugs called protease inhibitors which, among others, includes ritonavir (Norvir), nelfinavir (Viracept) and saquinavir (Invirase, Fortovase). Although both lopinavir and ritonavir inhibit the HIV virus, they are combined in Kaletra because ritonavir increases the concentration of lopinavir in the body. In fact, the activity of Kaletra against HIV is due to the lopinavir because the amount of ritonavir in Kaletra is not enough to inhibit the HIV virus.

During infection with HIV, the HIV virus multiplies within the body's cells. Viruses are released from the cells and spread throughout the body where they infect other cells. In this manner, HIV infection is perpetuated among new cells that the body produces continually. During the production of the viruses, new proteins for the viruses are made. Some of the proteins are structural proteins, that, is, proteins that form the body of the virus. Other proteins are enzymes which manufacture DNA and other components for the new viruses. Protease is the enzyme that forms the new structural proteins and enzymes. The lopinavir in Kaletra blocks the action of protease and results in the formation of defective viruses that are unable to infect the body's cells. As a result, the number of viruses in the body (the viral load) decreases. Nevertheless, Kaletra does not prevent the transmission of HIV among individuals, and it does not cure HIV infections or AIDS.

The lopinavir and ritonavir combination is under investigation for treatment of the COVID-19 coronavirus disease, a deadly respiratory infection pandemic caused by the SARS-nCoV-2 virus.

Most viruses have the ability to create proteins necessary for their life cycle. The lopinavir and ritonavir combination stops that process, in theory. For viruses to create their DNA or RNA (RNA in the case of SARS-nCov-2) the virus has to take control of some of the proteins in the host cell.

The virus relies on an enzyme called protease. Imagine the virus replication process as feeding dough into a pasta maker. The protease acts as a pair of scissors at the end, snipping off lengths of pasta as they come out of the machine to make the amino acids necessary for the virus to replicate itself.

What lopinavir and ritonavir aim to do as protease inhibitors is jam up that pair of scissors.

A lot of the experience with lopinavir and ritonavir, as with all the drugs the medical community is trying against the coronavirus pandemic, is drawn from the experience with the SARS outbreak in 2003. It was an option, but not clearly effective against the virus, according to trials done at the time. 

Unfortunately, nothing tried in the SARS and later MERS epidemics was obviously effective, but there were signals that some of these drugs might be useful.

As of this article’s publication date of April 7, 2020, the most recent study on lopinavir and ritonavir was published March 2020 in the New England Journal of Medicine where they compared lopinavir and ritonavir with the current standard of care (supportive care to alleviate symptoms with no antiviral medication). 

The conclusion was there was no increased benefit compared with the standard supportive care, but that study is not the last word on lopinavir and ritonavir's effectiveness against the SARS-nCoV-2 virus. Further studies are underway, including the World Health Organization's Solidarity study. This study allows healthcare providers around the world to provide observational data on a list of promising drugs now in use to help determine whether they really provide benefit or not.

The lopinavir and ritonavir combination is on that list, so doctors will know more as data comes in.

COVID-19 section data provided by Dominic Chan, a Pharm. D. and infectious disease specialist at Legacy Health System in Oregon.

The most common side effects of Kaletra are:

• abdominal pain,
• weakness,
• nausea,
• diarrhea,
• vomiting,
• headache and
• insomnia.

Kaletra may cause liver failure and failure of the pancreas. Like other protease inhibitors use of Kaletra may be associated with:

• redistribution or accumulation of body fat,
• increased cholesterol,
• worsening of diabetes, and
• abnormal heart rhythms.

Kaletra should be used cautiously in patients with pre-existing heart conditions.

Kaletra tablets may be administered with or without food. Oral solution and capsules should be administered with food. There are several dosing regimens depending on the formulation used, age of the patient, previous exposure to lopinavir, or use of other drugs. Here are some examples.

• Therapy-naive adult patients: 400/100 tablets (3 capsules) twice daily or 800/200 (6 capsules) once daily; Oral solution, 5 mL twice daily or 10 mL once daily with food.
• Therapy-experienced adult patients: 200/50 tablets, two twice daily or 3 capsules twice daily; Oral solution 5 mL twice daily. Once daily administration of Kaletra is not recommended.
• Children between 6 months and 18 years of age: The recommended dose is 230/57.5/m2 of the oral solution given twice daily and not to exceed the recommended adult dose. Kaletra should not be administered once daily in patients less than 18 years of age.
• Children between 14 days and 6 months of age: The recommended dose is 16/4/kg or 300/75/m2 of the oral solution given twice daily.
• In combination with efavirenz (Sustiva), nevirapine (Viramune), fosamprenavir (Lexiva) or nelfinavir (Viracept): Once daily administration is not recommended when combined with efavirenz, nevirapine, fosamprenavir or nelfinavir. For adults, the recommended dose is two 200/50 tablets and one 100/25 tablet twice daily; Oral solution, 6.5 mL twice daily. For children, the recommended dose is 300/75/m2 not to exceed the adult dose.

Kaletra interacts with many drugs. Some of the important interactions are mentioned below. Patients should consult their healthcare provider before combining any drug with Kaletra.

Kaletra should not be used together with amiodarone (Cordarone), quinidine (Quinaglute, Cardioquin), triazolam (Halcion), midazolam (Versed), pimozide (Orap), ergotamine derivatives (for example, Ergostat), propafenone (Rythmol) and flecainide (Tambocor) because Kaletra increases the levels of these drugs in the body and as a result may lead to serious adverse effects of these drugs.

Kaletra may also prevent the break down of lovastatin (Mevacor), simvastatin (Zocor), rosuvastatin (Crestor) and atorvastatin (Lipitor), causing their levels in the body to rise. This may increase the occurrence of muscle breakdown (rhabdomyolysis), which is a side effect of these drugs. Therefore, lovastatin and simvastatin should not be combined with Kaletra; the dose of rosuvastatin should not exceed 10 mg/day and the lowest dose of atorvastatin should be used. The blood concentration of rifabutin (Mycobutin) and sildenafil (Viagra) can be increased by Kaletra. Therefore, the doses of rifabutin and sildenafil should be reduced.

The oral solution contains alcohol, which causes severe side effects when combined with metronidazole (Flagyl) or disulfiram (Antabuse).

Kaletra can reduce the effectiveness of oral contraceptives.

Rifampin (Rifadin), St. John's wort, efavirenz (Sustiva) and nevirapine (Viramune) decrease the blood levels of Kaletra and this can reduce the effectiveness of Kaletra.

• Use of Kaletra during pregnancy has not been adequately evaluated.
• It is not known whether Kaletra is excreted in breast milk. Nevertheless, HIV-infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant that is not infected.

What preparations of lopinavir and ritonavir are available?

Tablets (mg lopinavir/mg ritonavir): 100/25 and 200/50. Oral solution: 80/20 per mL. Capsules: 133/33.3.

How should I keep lopinavir and ritonavir stored?

Capsules and solution should be refrigerated at 2 C to 8 C (36 F to 46 F). If stored at room temperature, the capsules and solution should be used within 2 months. Tablets should be stored at 15 C to 30 C (59 F to 86 F).