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How lopinavir works
Lopinavir and ritonavir are both members of the group of drugs referred to as protease inhibitors (Pis). This class of drug combats viral replication of HIV by blocking HIV's protease protein. This protein or enzyme is used by HIV to break up large viral proteins into smaller particles from which new HIV particles can be formed. Protease inhibitors ensure that these new particles are immature and incapable of infecting new cells, thus inhibiting the HIV replication process.
Lopinavir is co-formulated with ritonavir to boost blood levels of lopinavir. The boosting of lopinavir with ritonavir results in lopinavir being metabolised at a slower rate and ensuring therapeutic levels of lopinavir in the body.
History
Lopinavir/ritonavir was formerly known as ABT-378. Lopinavir/ritonavir was first licensed in Europe for adults and children over the age of two. The licence was granted for the use of lopinavir/ritonavir soft capsules or oral solution to be used in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children above the age of two.
Combination therapy
Lopinavir/ritonavir is established as an effective component of combination antiretroviral therapy against an optimal antiretroviral background, it should not be used as monotherapy as resistant viruses rapidly emerge.
Careful consideration needs to be given when incorporating lopinavir/ritonavir into combination therapy, as there are several known interactions with other antiretrovirals. These are considered later.
Dosing
Lopinavir/ritonavir is produced in soft orange capsules of 133.3mg of lopinavir co-formulated with 33.3mg of ritonavir. Each capsule features a black imprint of an "a" and "PK".
Lopinavir/ritonavir is also available in an oral solution for those who have difficulty swallowing capsules. Each 5ml of lopinavir/ritonavir solution contains 400mg lopinavir co-formulated with "l00mg of ritonavir. The solution is light yellow/golden in colour.
The recommended adult daily dose of lopinavir/ritonavir is three capsules taken orally twice daily with food and in combination with other antiretrovirals.
The recommended dose for children over two years of age is calculated on body surface area. Children with a body surface area of 1.3m2 or greater should take 3 capsules twice daily, with food. For children with a body surface area of less than 1.3m2, oral solution is recommended.
The recommended adult daily dose of lopinavir/ritonavir oral solution is 5ml (400mg of lopinavir/IOOmg of ritonavir), taken twice daily, with food. The recommended dose for children over two years of age is 230mg of lopinavir/57.5mg of ritonavir per m2 of body surface area.
This should be calculated using an oral dosing syringe. An increased dose may be necessary in children also receiving nevirapine or efavirenz.
Dosing restrictions
Lopinavir/ritonavir capsules and oral solution should be taken with food. There are several drug interactions with lopinavir/ritonavir that should be noted these include the following:
St. John's wort should not be taken alongside lopinavir/ritonavir as it reduces Lopinavir/ritonavir's efficacy
Dose increase of lopinavir/ritonavir will be necessary when it is co-administered with nevirapine or efavirenz (NNRTIs)
If lopinavir/ritonavir is used alongside the protease inhibitors indinavir, nelfinavir, saquinavir or amprenavir then drug concentrations will be increased requiring dose reduction
If lopinavir/ritonavir is co-administeredwith didanosine (ddl) then didanosine should be taken one hour before or two hours after lopinavir/ritonavir
Sildenafil (Viagra) levels in the body are increased in the presence of lopinavir/ritonavir, so its use is contraindicated with lopinavir/ritonavir
Co-administration of lopinavir/ritonavir and rifabutin (TB medication) results in increased blood levels of rifabutin, indicating a dose reduction of 75% every other day or 3 times per week
Rifampicin (TB medication) is not recommended to be used alongside lopinavir/ritonavir
Lopinavir/ritonavir may lower the concentration of methadone and monitoring of concentrations are recommended
Lopinavir/ritonavir inhibits the enzyme CYP3A, and should not be used with drugs that are dependent on this enzyme for clearance. These drugs include, terfanadine, midazolam, triazolam, cisapride, pimozide, amiodarone and ergot alkaloids
It is not recommended to use lopinavir/ritonavir alongside lovastatin orsimvastatin (lipid regulators); if lipidregulators are necessary pravastatin orfluvastatin are recommended
The efficacy of the oral contraceptive pill may be reduced in the presence of lopinavir/ritonavir, additional or alternative contraception should be considered.
Storage
Stocks of lopinavir/ritonavir capsules and oral solution should be refrigerated between 2°C and 8°C. If kept outside the refrigerator, capsules and oral solution should not be stored above 25°C and used within 42 days, after which time they should be discarded.
Side Effects
The most common side effects of lopinavir/ritonavir are those to the gastro-intestinal system. These include:
Nausea
Diarrhoea
Vomiting
Abdominal pain
Headache
Fatigue
Rash - especially in children
Insomnia
Other side effects associated with lopinavir/ritonavir and common to all the protease inhibitors include:
Lipodystrophy (although incidence and degree varies between all Pis)
Increase in blood fats
Elevated liver enzymes
Pancreatitis
Pre-existing conditions
Lopinavir/ritonavir should be used with caution in patients with mild to moderate liver impairment and should not be given to patients with severe liver impairment. Caution should also be taken when considering lopinavir/ritonavir with severe kidney impairment; mild to moderate impairment requires no dose adjustment.
Patients with bleeding disorders may require additional clotting agents. Patients currently treated for TB should only incorporate lopinavir/ritonavir in their regime with extreme care; drug interactions need to be considered.
Paediatric use
Lopinavir/ritonavir capsules and oral solution are licensed for use in children over two years of age. Lopinavir/ritonavir has not been studied in children under two years of age.
Use during pregnancy
There are no adequate and well-controlled studies of lopinavir/ritonavir in pregnant women. For this reason, lopinavir/ritonavir should only be used during pregnancy if the benefits justify potential risks. Mothers should be advised not to breastfeed their infants if receiving lopinavir/ritonavir.
Lopinavir/ritonavir-resistant HIV
It is widely accepted that all protease inhibitors experience an element of cross-resistance within the group.
Resistance to lopinavir/ritonavir is slow to develop; the maintained high levels of lopinavir achieved in the blood have explained this. Some evidence suggests that those who have experienced PI resistance may still benefit from lopinavir/ritonavir. A recent study that compared the emergence of resistance in patients receiving nelfinavir or lopinavir/ritonavir against a background regime of d4T/3TC after 60 weeks treatment revealed that no resistance developed in patients taking lopinavir/ritonavir compared to 37% in those taking nelfinavir.
