Lopinavir/ritonavir (Kaletra, Aluvia) is a protease inhibitor drug available in tablet and solution form. Lopinavir is marketed only with a boosting dose of ritonavir; ritonavir is marketed separately as Norvir.[ix] [ix] [ix]
Protease inhibitors block the activity of the HIV protease (or proteinase) enzyme to slow HIV replication and delay damage to the immune system.
Kaletra is made by Abbott Laboratories. 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.
A paediatric tablet formulation of the drug was approved for paediatric use in the US in 2007 and in the EU in 2008 containing 100mg lopinavir plus 25mg ritonavir. Unlike the the oral formulation, Kaletra tablets can be taken with or without food and do not require refrigeration.
Kaletra is a powerful anti-HIV drug. Studies suggest that approximately 75 to 90% of people who start treatment with Kaletra plus nucleoside reverse transcriptase inhibitors (NRTIs) achieve a viral load below 400 copies/ml after one year, and 70% maintain viral loads below 50 copies/ml after four years.[ref] [ref] [ref] [ref]
Some patients in the original study of Kaletra in treatment-naive patients have been taking the drug for over six years, with persistently undetectable viral loads.[ref] The strength of current evidence in favour of Kaletra has led experts in the United Kingdom and the United States to recommend Kaletra as a preferred first-line protease inhibitor[ix] [ix].
Kaletra-based regimens appear to be more potent than single protease inhibitor-based regimens in people who have not previously taken HIV treatment. For example, head-to-head studies have shown that Kaletra is more potent than nelfinavir (Viracept) and atazanavir (Reyataz).
K aletra has also been compared to other ritonavir (Norvir)-boosted protease inhibitors. For example, the MaxCmin2 study[ix] found that Kaletra is superior to ritonavir-boosted saquinavir (Invirase), with fewer people taking Kaletra dropping out due to side-effects.[ref] In contrast, the KLEAN study[ix] [ix] found that Kaletra is of similar effectiveness to ritonavir-boosted fosamprenavir (Telzir).[ref]
Studies conducted in people who have previously taken protease inhibitors also suggest that Kaletra has similar efficacy to other ritonavir-boosted protease inhibitors. One study found that Kaletra and ritonavir-boosted atazanavir had similar outcomes in terms of viral loads and CD4 cell counts, despite less favourable effects on blood lipids with Kaletra. [ref]
A comparative study of Kaletra and ritonavir-boosted fosamprenavir showed equivalence in terms of the proportion of people achieving undetectable viral loads, although Kaletra may be superior in terms of the magnitude of viral suppression.[ref] [ix] [ix]
In ACTG 5142[ix], patients received one of three regimens: efavirenz+ 2 NRTIs, Kaletra (LPV/r) + 2 NRTIs, or an NRTI-sparing combination of efavirenz and Kaletra. The NRTI options were 3TC or FTC combined with stavudine (d4T), TDF, or zidovudine (ZDV). At the start of the study, the median viral load was approximately 100,000 copies/ml and the median CD4 cell count was 182 cells/mm3, suggesting that the study population had relatively advanced HIV disease and was starting treatment later than current guidelines recommended.
By intent-to-treat analysis, 89% of the participants receiving efavirenz-based triple therapy had viral loads below 50 copies/ml after 96 weeks, as compared with 77% receiving Kaletra-based triple therapy.[ref]
The researchers were unclear why fewer participants on Kaletra-based triple therapy achieved viral loads below 50 copies/ml at week 96, compared with those on efavirenz-based triple therapy, since they found that the time to treatment-limiting toxicity was similar for all arms, and the proportion of grade 3 or 4 clinical adverse events was similar in each arm, at around 20%.
There is encouraging evidence that Kaletra is an effective component of salvage therapy[ix]. For example, Kaletra and nevirapine (Viramune) plus NRTIs suppressed viral load below 400 copies/ml in 70% patients after 48 weeks.[ref] Similar effects were observed when Kaletra was combined with efavirenz (Sustiva), with 65% of patients having undetectable viral loads after 48 weeks.[ref]
Studies have examined the effects of combining Kaletra with the protease inhibitors saquinavir, indinavir (Crixivan) and atazanavir, with results indicating that these combinations are safe and effective.[ref] [ref] [ref] [ref]
Because of its long half-life and high genetic barrier to resistance, Kaletra has been investigated as an option for monotherapy in treatment-naive and -experienced patients. At least three studies have demonstrated that switching from Kaletra or efavirenz (Sustiva) plus two NRTIs to Kaletra monotherapy leads 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.[ref] [ref] [ref] [ref] [ref] However, these trials have generally found inferior levels of viral suppression to trials of combination therapy including Kaletra. [ref]
MONARK, a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in treatment-naive HIV-infected 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.[ref]
The standard adult dose of Kaletra is two tablets (each containing 200mg lopinavir/50mg ritonavir) twice daily. An oral solution containing 80mg/ml LPV and 20mg/ml RTV is available and generally dosed twice daily. Each dose of 5ml contains 400mg LPV/100mg RTV. 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 Kaletra in a co-formulation (800mg/200mg) for patients new to HIV treatment. According to a press release from its manufacturer Abbott, Kaletra dosed once daily may be associated with a lesser sustainability of virologic suppression and a higher risk of diarrhoea compared to the recommended standard twice-daily dosage.[ref]
The 48-week results from the MO6-802 study showed that in treatment-experienced patients, there was no significant difference in viral load suppression or side-effects between patients who took the drug once or twice daily.[ref]
A particular concern in once-daily dosing is the risk of lopinavir levels falling to low levels between once-daily doses. This occurred in six of 20 patients in one study and only dose escalation was able to resolve the problem in one patient.[ref]
A later 48-week long ACTG 5073 study[ix] (AIDS Clinical Trials Group) found no difference in the probability of achieving sustained virological response between the once-daily and twice-daily arms of the study. However, in those who entered the study with a higher viral load, a significantly higher proportion of patients receiving twice-daily therapy achieved a sustained response than did patients taking Kaletra once daily.[ref]
In the ARTEMIS study, another 48-week study reported on in 2007, more patients in the twice-daily lopinavir/r arm achieved a viral load less than 50 copies/ml than did those on once-daily dosing. Additionally, participants in the once-daily dosing arm experienced more gastrointestinal adverse events and diarrhoea.[ref]
However, the MO5-739 study looking at dosing frequency found that at 48-weeks, Kaletra tablets dosed once daily were no less safe and effective than twice-daily dosing. Each study arm received Kaletra in combination with Truvada and after a year, an equal number of patients in both study arms had undetectable viral load and comparable CD4 cell count increases. In this study, once-daily Kaletra did not increase the risk of side-effects (including diarrhoea).[ref]
Kaletra was originally available in capsules containing 133mg LPV/33.3mg RTV, with a standard dose being three capsules twice a day. Lopinavir/ritonavir in capsule and oral solution form was approved by the US FDA in 2000 for use with other antiretrovirals in the treatment of adults and children 6 months of age or older. Marketing approval in the EU followed soon after. The film-coated tablet was approved in the US in 2005 and in the European Union in 2006. In developing and middle-income countries[ix], the tablets are marketed under the trade name Aluvia. Tablets cannot be crushed or split; they must be taken whole.
The tablet formulation produces equivalent exposure and maximal blood concentrations of both drugs to the capsules. It also carries a lower risk of causing extreme peaks and troughs in blood drug levels.[ref]
The approval of a low-dose tablet (100mg lopinavir/25mg ritonavir) in both the EU and the US should make it easier for patients on non-standard dosing schedules to achieve the correct blood levels of both drugs.
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%.
The commonest side-effects of Kaletra are diarrhoea and nausea. In the major studies of Kaletra, moderate or severe diarrhoea affected 12 to 27% of participants. Two to 7% of patients interrupted therapy because of diarrhoea, but only 1% of all participants in these trials stopped Kaletra treatment. 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[ix] [ix] [ix] [ix].
Fatigue, muscle weakness, headache, stomach pain and vomiting are less common side-effects associated with Kaletra in clinical trials.
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 (Viracept).[ref] However in another study, 35% of patients experienced body fat changes after four years on Kaletra. [ref]
Elevated lipids, including high triglycerides and cholesterol levels, occur amongst 10 to 25% of people on Kaletra, particularly among those with high cholesterol or triglycerides before starting to take the drug.[ref] [ref] [ref] [ref]
These lipid changes are mild in the majority of patients and only rarely lead to treatment discontinuation.[ref] [ref] There seems to be no correlation between blood concentrations of lopinavir and the severity of lipid elevations, suggesting that dose reductions are unlikely to moderate lipid increases.[ref] The low-dose ritonavir, rather than the lopinavir in Kaletra drives the increases in blood cholesterol and triglyceride levels.[ref] Kaletra is also associated with insulin resistance and the development of type II diabetes.[ref]
The other key side-effect associated with Kaletra is elevated liver enzyme levels, which occurs most commonly among individuals co-infected with hepatitis B or C.[ref] [ref] [ref] As observed for lipid elevations, liver toxicity does not seem to be related to the levels of lopinavir in the blood, suggesting that dose adjustments are unlikely to be of benefit.[ref] However, liver problems are rare in patients taking Kaletra, with one study finding an incidence of severe liver abnormalities of less than one per 100 person-years of treatment.[ref]
In ACTG 5142, lipoatrophy (defined as a 20% loss of limb fat at week 96), was experienced by 32% of the efavirenz + 2NRTI group, 17% of the Kaletra + 2 NRTI group, and 9% of the Kaletra/efavirenz group.[ref]
When the incidence of lipoatrophy was analysed according to the second nucleoside analogue used, it was most commonly seen in patients who received d4T, 42% compared to 27% in the AZT group. Just 9% of tenofovir-treated patients developed lipoatrophy, a significantly lower proportion than was found in the AZT recipients.
Compared to EFV, LPV had less lipoatrophy when given with an NRTI. When lipoatrophy incidence was analysed according to pairings of drugs, it was evident that tenofovir recipients who received efavirenz were more likely to develop lipoatrophy (12%) than those who received Kaletra (6%). Similarly, AZT recipients who received efavirenz were also at greater risk of lipoatrophy (40% vs 16% for Kaletra recipients). The difference was less pronounced for d4T recipients (51% for efavirenz, 33% for Kaletra).
After 96 weeks those in the nucleoside-sparing arm had experienced an average 18% gain in limb fat (around 1kg), compared to a 9.8% gain in the Kaletra + 2 NRTIs group and a gain of 1.4% in the efavirenz group.
A surprising result was that the NRTI-sparing regimen (LPV+EFV) increased lipids significantly more than did the EFV+2 NRTIs or LPV+2 NRTIs regimens. Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but cholesterol changes were not significantly different.
Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but cholesterol elevations between the Kaletra and efavirenz arms were similar. The increase in HDL cholesterol was significantly greater in the Kaletra/efavirenz nucleoside-sparing arm.
As with all other anti-HIV drugs, strains of HIV that are resistant to Kaletra may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug[ix] [ix].
There has been a large number of publications describing patients with prior protease inhibitors experience who have failed lopinavir treatment. However, Kaletra has a high genetic barrier to lopinavir resistance and is very effective in protease inhibitor-experienced patients, making it difficult to ascertain the combination of mutations necessary for Kaletra therapy to fail.
To date, reduced sensitivity to Kaletra has been mainly associated with mutations 46I, 54V, 71V, 82A and 84V.[ref] [ref] [ref] Other mutations which have been associated with resistance to Kaletra include L10F/I/R/V and L90M, as well as mutations at codons 20, 24, 32, 33, 46, 47, 50, 53, 63 and 90.[ref] [ref] [ref] [ref] One study reported that having five or more mutations at these positions or positions 33, 36, or 48 is associated with complete resistance to Kaletra, while having three or four of these mutations is linked to mild resistance.[ref] V47A also causes resistance to Kaletra in patients infected with HIV-2.[ref]
All of the protease inhibitors are, to some extent, cross-resistant. This means that resistance mutations that emerge in the presence of one protease inhibitor reduce the effectiveness of other protease inhibitors. There is evidence that HIV with reduced susceptibility to Kaletra shows high-level resistance to indinavir (Crixivan) and ritonavir, intermediate resistance to amprenavir (Agenerase) and susceptibility to saquinavir (Invirase).[ref]
Both lopinavir and ritonavir interact with many other drugs, including some anti-HIV drugs. Consequently, patients taking Kaletra should avoid, or alter the dose of other drugs they are taking[ix].
Since both lopinavir and ritonavir are inhibitors of the enzyme CYP3A4, the following drugs should not be taken alongside Kaletra:
- Amiodarone (Cordarone X)
- Colchicine in patients with renal or hepatic impairment
- Ergotamine tartrate (Cafergot / Migril)
- Flecainide (Tambocor)
- Hypericin (St John’s wort)
- Midazolam (Hypnovel)
- Pimozide (Orap)
- Propafenone (Arythmol)
- Rifampicin (Rifadin / Rimactane)
- Simvastatin (Zocor)
- Voriconazole (Vfend).
Kaletra interacts with many other anti-HIV drugs, and requires non-standard doses to be used. Kaletra boosts the levels of other protease inhibitors:
- Fosamprenavir (Telzir) interacts with Kaletra, with exposure to both drugs being reduced by more than half.[ref] Treatment-experienced patients should take an increased dose of three Kaletra tablets twice a day. There is no recommended dose adjustment for treatment-naive patients or for patients taking Kaletra capsules. This interaction is not overcome by separating the doses of the drugs.[ref]
- Indinavir (Crixivan) should be taken at a dose of 600mg twice a day.
- Nelfinavir (Viracept): treatment-experienced patients need to take an increased dose of four capsules or three tablets of Kaletra twice a day.
- Saquinavir (Invirase) should be taken at a dose of 1000mg twice a day.
- Tipranavir (Aptivus) reduces the levels of lopinavir when both drugs are boosted with ritonavir.[ref] Further studies need to be done to ascertain how drug doses should be adjusted to counteract this effect.
Increasing the dose of Kaletra to four capsules or three tablets twice daily when co-administered with efavirenz (Sustiva) or nevirapine (Viramune) is necessary for treatment-experienced patients.[ref]
Kaletra must not be administered once daily in combination with efavirenz, nevirapine, nelfinavir, amprenavir, carbamazepine, phenobarbital or phenytoin.
Concentrations of the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (Viread) are slightly elevated when taken in combination with Kaletra. Although this does not produce an increased risk of kidney toxicity, patients taking both drugs should be monitored closely for the development of side-effects.[ref] Tenofovir has also been shown to reduce lopinavir levels. A dose increase to four capsules or three tablets twice a day may be necessary.[ref]
ddI (didanosine, Videx) should be taken one hour before or two hours after Kaletra capsules, but can be taken at the same time as Kaletra tablets.
Patients taking the following drugs and Kaletra need to adjust the doses of one or both drugs, or to take the drugs with caution:
- Bepedril levels are increased by Kaletra, so it should be used with caution.
- Carbamazepine (Tegretol) should be used with caution, as combining it with Kaletra can cause including drowsiness and unsteadiness.[ref]
- Chlorphenamine maleate (Piriton) can affect the heart in patients taking Kaletra, so it should be used with caution.
- Ciclosporin (Neoral / Sandimmun) levels are increased by Kaletra. In one study, dose reductions of 5 to 20% were required to maintain target drug concentrations.[ref]
- Clarithromycin (Klaricid / Klaricid XL) levels are significantly increased by Kaletra and dose adjustment may be required if kidney problems occur. This drug also can affect the heart in patients taking Kaletra.
- Erythromycin (Erymax / Erythrocin / Erythroped / Erythoped A) can affect the heart in patients taking Kaletra, so it should be used with caution.
- Felodipine (Plendil) levels are increased by Kaletra, so it should be used with caution.
- Fluticasone propionate (Flixotide) levels are increased by Kaletra, raising the risk of side-effects such as weight gain, excess sweating and thinning of the skin.
- Lidocaine (Minijet Lignocaine) levels are increased by Kaletra, so it should be used with caution.
- Ketoconazole (Nizoral) and Kaletra should be co-administered with caution. The dose of ketoconazole should not exceed 200mg daily.
- Methadone hydrochloride (Methadose) increases concentrations of ritonavir but this effect is blunted when it is dosed with Kaletra.[ref] However, Kaletra may decrease concentrations of methadone, so monitoring of methadone blood concentrations and withdrawal symptoms is advised.[ref]
- Nicardipine (Cardene) levels are increased by Kaletra, so it should be used with caution.
- Nifedipine (Adalat) levels are increased by Kaletra, so it should be used with caution.
- Phenobarbital should be used with caution by patients also taking Kaletra.
- Phenytoin (Epanutin) should be taken with a higher dose of Kalet ra of 533mg lopinavir with 133mg ritonavir, or with an extra 100mg ritonavir (Norvir). Levels of phenytoin in the blood should be monitored, if possible.[ref]
- Quinidine (Kinidin Dureles) levels are increased by Kaletra, and quinidine can affect the heart in patients taking Kaletra. It should be used with caution.
- Rifabutin (Mycobutin) levels are increased by Kaletra. Doses should be reduced to 150mg.[ref]
- Sildenafil (Viagra) concentrations are significantly increased by ritonavir. Concurrent use of Kaletra and sildenafil should be used with caution, to avoid the risk of sildenafil-associated side-effects. Sildenafil should be started at a dose of 25mg and increased every two days, while close monitoring occurs. Sildenafil is contraindicated if used for treatment of pulmonary arterial hypertension, due to dose required.
- Tacrolimus (Prograf) levels are increased by Kaletra, so should be used with caution.
- Tadalafil (Cialis) should be taken at reduced doses of 10mg every 72 hours
- Vardenafil (Levitra) should be taken at no more than 2.5mg every 72 hours.
- Warfarin levels are increased by Kaletra, so should be used with caution.
In 2008, the US FDA approved the use of Kaletra (LPV/RTV)) in children 14 days of age and older. In the European Union, the drug is indicated for children two years and older, dosed by weight, in combination with other ARVs. EU marketing approval for the low-dose tablet was given in 2008.
The liquid formulation is highly concentrated, contains 80mg LPV/20mg RTV per ml, should be taken with food, and never exceed a dose of 5ml twice daily. The low-dose paediatric tablet contains 100mg LPV/25mg RTV (half the standard adult dose) and can be taken with or without food as part of a HAART regimen. Neither formulation requires refrigeration. Once-daily dosing is not advised in children.
Paediatric dosing is based on body weight (kg) or body surface area (BSA per m2) up to 40 kilos. Dosing for infants aged 14 days to six months using the liquid formulation is twice daily at 300mg LPV per m2 BSA/75mg RTV per m2 BSA. By weight, dosing is 16mg LPV per kg/4mg RTV per kg. In this age group, co-administration of efavirenz, nevirapine, fosamprenavir, or nelfinavir is not recommended.[ref]
The US paediatric guidelines warn that use of 300mg LPV per m2 in those under six months of age, and particularly in those under six weeks of age, is associated with lower trough levels than are found in adults. Consequently, infants need to be evaluated frequently for dose adjustments. After an infant died from an overdose on the liquid solution in 2007, Abbott sent out an advisory reminding physicians that Kaletra in children must be calculated by body weight until the child is 40 kilos and should never exceed 5ml, given twice daily.
After six months, dosing by BSA per m2 is 230mg LPV/57.5mg RTV twice daily. If dosing by weight, children <15 kilos would receive 12mg/LPV per kg/3mg RTV per /kg twice daily. In children 15 to 40 kilos, dosing is 10mg LPV per kg/2.5mg RTV per kg twice daily.
Using the low-dose tablets (100mg LPV/25mg RTV), children would receive twice-daily dosing per kilo or by BSA (m2) as follows:
- 2 tablets for those 15 to 25 kilos or BSA ≥0.6 to <0.9
- 3 tablets for those >25 to 35 kilos or BSA ≥0.9 to 1.4
- 4 tablets for those >35 kilos or BSA ≥1.4 or 2 full-strength (200mg LPV/50mg RTV) tablets.
This dosing would need to be adjusted in children aged 6 months to 18 years if they were also receiving efavirenz, nevirapine, fosamprenavir, or nelfinavir. Again using the low-dose tablets, children would receive twice-daily dosing per kilo or by BSA (m2) as follows:
- 2 tablet for those 15 to 20 kilos or BSA ≥0.6 to <0.8
- 3 tablets for those >20 to 30 kilos or BSA ≥0.8 to 1.2
- 4 tablets for those >30 to 45 kilos or BSA ≥1.2 to <1.7 (or 2 full-strength tablets)
- 4 tablets for those >45 kilos or BSA ≥1.7 (or 2 full-strength doses). In ARV-experienced patients with suspected or confirmed loss of sensitivity to LPV, 6 low-dose tablets (or 3 full-strength) may be given.
The package insert information should be consulted for more detailed directions.
Once-daily dosing was attempted in one study in children using a dose of 460mg/m2 lopinavir and 155mg/m2 and this produced similar levels of lopinavir to the 800mg /200mg once-daily dose used in adults. However, given the high variability in LPV drug exposure and trough plasma concentrations amongst individuals, paediatric once-daily dosing is not currently recommended. [ref]
A number of studies have confirmed that use of the liquid formulation of Kaletra can reduce viral loads in children who have never taken antiretroviral drugs before, as well as those who are ARV-experienced.[ref] [ref]
The side-effect profile of Kaletra is similar in children and adults.
In the US, Kaletra is one of several recommended first-line PI components in regimens for children. WHO recommends it for use, along with two NRTIs, in infants under 12 months of age who have nevirapine exposure. In children 12 months or older, initial ART with either nevirapine or efavirenz plus two NRTIs is recommended over a PI-based initial regimen.
The safety of Kaletra in pregnant women has not been established, but animal studies have shown some toxicity. Lopinavir also crosses the placenta, reaching effective anti-HIV levels in the foetus.[ref] Kaletra should not be used in pregnancy unless clearly necessary.