Lopinavir/ritonavir

Lopinavir/ritonavir is a protease inhibitor drug available in tablet and solution form. Lopinavir is only available together with a boosting dose of ritonavir.

Protease inhibitors block the activity of the HIV protease (or proteinase) enzyme to slow HIV replication and delay damage to the immune system.

Lopinavir was developed under the codename ABT-378 and approved for marketing in the United States in 2000 and in the European Union in 2001. A heat-stable, film-coated tablet was approved in the US in 2005 and in the EU in 2006, replacing the original gelatin capsule. Each tablet contains 200mg lopinavir plus 50mg ritonavir. Lopinvair/ritonavir is marketed as Kaletra by AbbVie. Several generic versions of lopinavir/ritonavir are also available.

Effectiveness

Lopinavir/ritonavir is no longer recommended for people starting antiretroviral treatment, as better tolerated, more potent alternatives are now available. The use of lopinavir/ritonavir in second-line treatment varies according to location:

• In lower- and middle-income settings, lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended regimen for second-line treatment after failure of an integrase inhibitor- or NNRTI-containing regimen. (WHO)
• In higher-income settings (Europe, North America, Japan, Australasia), lopinavir/ritonavir may be used as an alternative to boosted darunavir in second-line treatment. However, treatment guidelines recommend that better tolerated agents such as boosted darunavir or an integrase inhibitor should be used in preference to lopinavir/ritonavir.

Studies suggest that approximately 75 to 90% of people who start treatment with lopinavir/ritonavir plus NRTIs achieve a viral load below 400 copies/ml after one year, and 70% maintain viral loads below 50 copies/ml after four years. (Murphy) (Walmsley) (Lichterfeld) (Hicks)

Lopinavir/ritonavir has been compared to other ritonavir-boosted protease inhibitors in previously untreated people. For example, the MaxCmin2 study found that lopinavir/ritonavir is superior to ritonavir-boosted saquinavir (Invirase), with fewer people taking lopinavir/ritonavir dropping out due to side effects. (Dragsted) The CASTLE study showed that twice-daily lopinavir/ritonavir was equivalent to once-daily atazanavir in viral suppression after 48 weeks, although gastrointestinal side effects were more frequent in lopinavir/ritonavir recipients. (Molina) However, the ARTEMIS study found that while lopinavir/ritonavir and darunavir/ritonavir were equivalent in people with baseline viral loads below 100,000 copies/ml after 48 weeks, lopinavir/ritonavir was inferior to darunavir/ritonavir in those with viral loads above 100,000 copies/ml. (Ortiz)

Studies conducted in people who have previously taken protease inhibitors also suggest that lopinavir/ritonavir has similar efficacy to other ritonavir-boosted protease inhibitors. One study found that lopinavir/ritonavir and ritonavir-boosted atazanavir had similar outcomes in terms of viral loads and CD4 cell counts, despite less favourable effects on blood lipids with lopinavir/ritonavir. (Johnson)

A randomised study in Cameroon, Senegal and Burkina Faso found that when combined with tenofovir and emtricitabine, lopinavir/ritonavir produced an equivalent rate of viral suppression to darunavir/ritonavir after failure of the first antiretroviral regimen (69% vs 63% below 50 copies after 48 weeks). (Ciaffi)

Because of its long half-life and high genetic barrier to resistance, lopinavir/ritonavir was investigated as an option for monotherapy in treatment-naive and -experienced patients. Several studies demonstrated that switching from lopinavir/ritonavir or efavirenz plus two NRTIs to lopinavir/ritonavir monotherapy led to comparable virologic outcomes to patients randomised to remain on triple therapy after up to 48 weeks, with similar rates of resistance and blood fat elevations. (Arribas, IAS 2005) (Campo) (Nunes) (Cameron) (Arribas, IAC 2006)

MONARK was a prospective, open-label, randomised, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen for treatment-naive patients with HIV-RNA levels less than 100,000 copies/ml. At the week 48 on-treatment analysis, 80% in the monotherapy group and 95% of those on triple therapy achieved a viral load less than 400 copies/ml (intent to treat analysis was 64 v 75% respectively). This indicates that monotherapy should not be considered as a preferred treatment option for use in antiretroviral-naive patients. (Delfraissy)

A meta-analysis of ten randomised studies of protease inhibitor monotherapy (lopinavir/ritonavir was the agent in seven) found a small but statistically significant reduction in virological suppression, compared to combination antiretroviral therapy. When viral rebound occurred, it could usually be reversed by reintroducing NRTIs. There were no differences in the frequency of emergence of viral resistance or of serious adverse events. (Mathis)

Lopinavir/ritonavir has also been tested as part of a two-drug regimen, in combination with lamivudine. The GARDEL study showed that lopinavir/ritonavir and lamivudine resulted in equivalent viral suppression after 48 weeks when compared to lopinavir/ritonavir plus two NRTIs in previously untreated people. (Cahn)

Studies have shown that levels of lopinavir in the cerebrospinal fluid are low, but they are sufficient to inhibit HIV replication in patients who are adherent to lopinavir/ritonavir . (Capparelli) (Yilmaz) (Martin)

Taking it

The standard adult dose of lopinavir/ritonavir is two tablets (each containing 200mg lopinavir/50mg ritonavir) twice daily. For adults taking antiretroviral treatment for the first time, it can also be taken as four tablets once daily.

An oral solution containing 80mg/ml lopinavir and 20mg/ml ritonavir is available and generally dosed twice daily. Each dose of 5ml contains 400mg lopinavir/100mg ritonavir. The oral solution contains 42% alcohol, needs to be refrigerated, and should be taken with food.

In 2009, the European Medicines Agency approved once-daily dosing of lopinavir/ritonavir  (800mg/200mg) for patients new to HIV treatment. Once-daily dosing is not recommended for people with three or more protease inhibitor resistance mutations. 

Once-daily dosing of lopinavir/ritonavir was approved in the US for treatment-naive adults in April 2010 for patients with less than three lopinavir-associated resistance mutations. (Eron, 2004) A meta-analysis of trials comparing once- to twice-daily lopinavir/ritonavir in previously untreated people found no difference in virological suppression, failure rates or adverse events. (van Wijk)

Side effects

The commonest side effects of lopinavir/ritonavir are diarrhoea and nausea. In the major studies of lopinavir/ritonavir, moderate or severe diarrhoea affected 12 to 27% of participants.  Diarrhoea and loose stools are most common during the first two months of treatment, but many people experience ongoing problems. Nausea related to lopinavir treatment is also a common reason for interrupting treatment, occurring in 2 to 12% of study participants.

Other common side effects of lopinavir/ritonavir are nose or throat infections, anaemia, low white blood cell count, pancreatitis, vomiting, abdominal pain, bloating, flatulence, heartburn and indigestion, gastric reflux, flatulence, loss of appetite, raised lipids or blood sugar, diabetes, high blood pressure, rash, itching, skin infections, night sweats, dizziness, tiredness, difficulty in sleeping, anxiety, weakness, headache, haemorrhoids, raised liver enzymes, allergic reaction including swelling, erectile dysfunction, menstrual disorders, peripheral nerve damage and muscle and joint pain.

Body fat changes and metabolic disorders have been associated with the protease inhibitors as a class. After 60 weeks on lopinavir, 7% of HIV-positive individuals in a major international study had developed body fat changes, the same rate of development as seen among people who received nelfinavir. (Bernstein) However, in another study, 35% of patients experienced body fat changes after four years on lopinavir/ritonavir. (Hicks)

A comparison of lopinavir/ritonavir and efavirenz in the ACTG 5142 study showed that regardless of NRTI backbone, people randomised to lopinavir/ritonavir were less likely to suffer severe loss of body fat after 96 weeks on treatment than people receiving efavirenz. Those receiving an NRTI-sparing regimen of lopinavir/ritonavir and efavirenz lost least body fat. (Haubrich)

Elevated lipids, including high triglycerides and cholesterol levels, occur in 10 to 25% of people on lopinavir/ritonavir, particularly among those with high cholesterol or triglycerides before starting to take the drug. (Hicks) (Martinez) (Montes) (Valerio)

These lipid changes are mild in the majority of patients and only rarely lead to treatment discontinuation. (Lafeuillade) (Bongiovanni)

The other key laboratory side effect associated with lopinavir/ritonavir is elevated liver enzyme levels, which occurs most commonly among individuals co-infected with hepatitis B or C. (Hicks) (Meraviglia) However, liver problems are rare in patients taking lopinavir/ritonavir, with one study finding an incidence of severe liver abnormalities of less than one per 100 person-years of treatment. (Bonfanti)

Caution should be exercised in patients with hepatitis C co-infection, as mild to moderate hepatic impairment can increase blood levels of lopinavir by 30%.

Resistance

The most common protease mutations developing after failure of a regimen containing lopinavir/ritonavir are I54V, M46I, V82A and L76V. The protease inhibitors darunavir or tipranavir are likely to remain active against HIV with resistance to lopinavir. (Barber)

Drug interactions

Both lopinavir and ritonavir interact with many other drugs, including some anti-HIV drugs. Consequently, patients taking lopinavir/ritonavir should avoid or alter the dose of other drugs they are taking.

You should not take lopinavir/ritonavir with any of the following drugs:

• abemaciclib
• alfuzosin
• amiodarone
• apalutamide
• astemizole
• atorvastatin
• avanafil
• bedaquiline
• cisapride
• colchicine
• dihydroergotamine
• dronedarone
• elbasvir/grazoprevir
• ergonovine
• ergotamine
• fusidic acid
• itraconazole (higher doses)
• ketoconazole (higher doses)
• lovastatin
• lurasidone
• ombitasvir/paritaprevir/ritonavir
• methylergonovine
• midazolam taken orally
• neratinib
• pimozide
• quetiapine
• ranolazine
• rifampicin
• riociguat
• rivaroxaban
• salmeterol
• sildenafil (for hypertension)
• simvastatin
• St John's wort
• vardenafil
• venetoclax
• voropaxar.

Sildenafil is a drug used to treat pulmonary arterial hypertension (high blood pressure in the lungs). You should not take sildenafil with lopinavir/ritonavir if sildenafil was prescribed for this reason. Sildenafil (Viagra) is also used to treat erectile dysfunction (impotence). If you are using sildenafil for erectile dysfunction, tell your doctor before you start treatment with lopinavir/ritonavir.

The following antiretroviral drugs should not be used with lopinavir/ritonavir:

• fosamprenavir or fosameprenavir/ritonavir
• tipranavir/ritonavir.

The following drugs for treatment of hepatitis C should not be used with lopinavir/ritonavir:

• elbasvir/grazoprevir
• glecaprevir/pibrentasvir

• ombitasvir/paritaprevir/ritonavir + dasabuvir
• sofosbuvir/velpatasvir/ voxilaprevir.

Children

In Europe, lopinavir/ritonavir is recommended as a preferred first-line option for children aged 2 weeks to 3 years of age and an alternative option in children aged 3-6 years. United States guidelines recommend lopinavir/ritonavir only in infants aged 14 days to 4 weeks. The World Health Organization no longer recommends the use of lopinavir/ritonavir in first-line treatment for children.

Lopinavir/ritonavir is available in a liquid or tablet formulation for children. The tablet formulation is suitable for children weighing 10kg or more. Oral pellets or granules containing lopinavir/ritonavir are available in resource-limited settings. Lopinavir/ritonavir is dosed by weight in children; please refer to the package insert for dosing information.

Pregnancy

Lopinavir/ritonavir is no longer recommended for treatment in pregnant women in British, US or World Health Organization guidelines due to the availability of better tolerated alternatives.