Reduced dose of Kaletra soft-gel capsule effective in small study (corrected)

Researchers from Paris have found that it may be possible to reduce the standard dose of lopinavir/ritonavir soft-gel capsules (Kaletra) from three capsules twice daily to two capsules twice daily. However, viral load “blips” were frequently seen in people taking the reduced dose, and therapeutic drug level monitoring (TDM) is recommended. Results from a trial of dose reduction, called Kaledose, were presented last week at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco.

Although the new hard tablet formulation of Kaletra has recently become available in the United States and European Union soft-gel Kaletra is still being used elsewhere in the world until the new formulation becomes available. To date, the drug's manufacturer, Abbott, has filed for registration of the new tablet formulation in countries in Africa, Asia and Latin America.

It is important to note that this trial only studied the soft-gel formulation of lopinavir/ritonavir (LPV/r) which contains 133.3 mg lopinavir and 33.3 mg ritonavir in each capsule. The standard dose is three capsules twice daily, providing 400mg of lopinavir boosted with 100mg of ritonavir twice a day. This study examined two soft-gel capsules twice daily, providing 266.6mg of lopinavir and 66.6mg of ritonavir twice a day.

Plasma drug levels (the drug concentration in the bloodstream) vary with time: they peak shortly after the drug is taken, then slowly taper off until the next dose. The ‘trough concentration’ or C_min – the lowest level reached between doses – is a particularly important measurement. For antiretrovirals to remain active, trough levels must stay above the minimum effective concentration. However, the higher the C_min, the more severe the side-effects are likely to be.

For treatment-naïve patients (with no history of drug resistance or treatment failure), the recommended lopinavir trough concentration (C_min) is 3000 ng/mL (nanograms per milliliter). Over half the patients in a database kept by the study investigators had lopinavir C_min levels of 5000 ng/mL or more. This led the researchers to believe that lower doses of LPV/r might be safe and effective, and lead to fewer side-effects.

The study group enrolled adults on a treatment combination that included LPV/r. None had ever taken any other protease inhibitors. (Some had previously been on NNRTI-based therapies; none were taking NNRTIs during this study.) All had maintained an undetectable viral load (less than 50 copies/mL) for at least three months, and were tested to ensure they had LPV C_min levels of more than 5000 ng/mL. Average CD4 count was 346 cells/mm³, average age was 44.6 years, and people had been HIV-infected an average of 5.2 years.

Out of 33 initial participants, five dropped out during the study, leaving a total of 28 at the 48-week endpoint. The reduced dose resulted in lower trough LPV concentrations – an average of 4319 ng/mL, down from 7363; with 1427 ng/mL being the lowest level observed. At the end of the study, three out of the 28 participants had detectable viral loads (80, 160, and 1842 copies/mL).

However, over the course of the study, the investigators report that a proportion of participants experienced viral load ‘blips’ - single measurements above 50 copies/ml that returned to below 50 copies/ml two weeks later.

Unfortunately, the investigators’ report is inconsistent, and either eight out of the 28 participants experienced a total of thirteen viral load ‘blips’, or thirteen of the 28 participants experienced a total of 18 viral load ‘blips’. None of the blips were greater than 2000 copies/mL, and the majority were between 51 and 100 copies/ml. The investigators state that they did not find any significant differences in lopinavir C_min levels in the people whose viral loads ‘blipped’; in fact, they were not able to find any specific factors that identified the people at risk of ‘blips’.

Over the 48 weeks, blood triglyceride levels went significantly down (from an average of 1.73 mmol/L to less than 1.4 mmol/L). Two episodes of gastrointestinal problems were reported. A more detailed report on side-effects and quality of life was not presented; the analysis is still ongoing.

The researchers concluded that “a reduced dosing of LPV/r in patients without previous failure of PI containing regimen[s] and with C_min > 5000 ng/mL is associated with a sustained virological response. Nevertheless, this strategy is associated with episodes of ‘blips’. Therapeutic drug monitoring and [viral load] control is recommended in this type of strategy.”