CROI: Once daily Kaletra tablets non-inferior to twice daily dose

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Kaletra tablets dosed once daily are no less safe and effective than dosing the drug twice daily, according to a poster presented to the Fifteenth Conference on Retroviruses and Opportunistic Infection in Boston.

In the study, treatment-naïve patients were randomised to receive Kaletra tablets once daily (in a dose of 800mg lopinavir/200mg ritonavir) or twice a day (each dose consisting of 400mg/100mg lopinavir/ritonavir) in combination with Truvada. After a year, equal number of patients in the two arms of the study had an undetectable viral load and increases in CD4 cell count were also comparable. Taking once daily Kaletra tablets did not increase the risk of side-effects, including diarrhoea, a side-effect that is particularly associated with the drug.

Kaletra (lopinavir/ritonavir) was originally approved for twice daily dosing. An earlier study compared outcomes in treatment-naïve patients taking the soft-gel formulation of the drug once or twice daily. This showed that once daily dosing was non-inferior, although rates of diarrhoea were higher in the once-daily arm.



Abnormal bowel movements, characterised by loose, watery or frequent stools, three or more times a day.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.


In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.

non-inferiority trial

A clinical trial which aims to demonstrate that a new treatment is not worse than another. While the two drugs may have comparable results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 


A person who has never taken treatment for a condition.

Since this study was conducted Kaletra has been reformulated into a tablet. The tablet formulation involves a lower pill burden, and unlike the soft gel formulation the tablets do not need to be kept in the fridge and can be taken with or without food.

Investigators wished to see if Kaletra tablets were as safe and effective one daily as twice daily. They therefore designed a study to see if once daily dosing was non-inferior to twice daily dosing. Non-inferiority is a statistical means of clinical trial analysis that is used to demonstrate that one drug performs no worse than the other, within a specified margin of error.

A total of 664 HIV-positive individuals who had never taken antiretroviral therapy were enrolled to the study. All had a viral load above 1000 copies/ml and were randomised on an equal basis into one of four study arms: soft gel Kaletra twice daily; soft-gel Kaletra once daily; Kaletra tablets twice daily; or, Kaletra tablets once daily.

After eight weeks the patients taking both doses of the soft gel formulation of Kaletra were switched to the corresponding tablet dose of the drug.

Most of the patients (78%) were male and Caucasian (75%). Mean viral load at baseline was approximately 100,000 copies/ml, and on entry to the study mean CD4 cell count was 215 cells/mm3.

After 48 weeks of treatment an equal proportion of patients taking Kaletra once (78%) and twice daily (77%) had a viral load below 50 copies/ml. This confirmed the virological non-inferiority of once daily Kaletra tablets.

Further analysis showed that once and twice daily Kaletra tablets were equally likely to suppress viral load to undetectable levels in patients with low CD4 cell counts at baseline (below 50 cells/mm3), and that the two doses of the drug had equal virological efficacy in patients with a viral load above 100,000 copies/ml on entry to the study.

CD4 cell counts increased by 186 cells/mm3 in the once daily treated patients and 197 cells/mm3 in the patients taking Kaletra twice a day after a year.

No patient developed resistance to either lopinavir or tenofovir, although three patients did develop the M184V mutation that confers resistance to FTC. The investigators do not specify which dose(s) of Kaletra these patients received.

Rates of moderate to severe diarrhoea were similar between patients taking treatment once a day (17%) and twice a day (15%). This finding was at odds with the findings of the study involving patients taking Kaletra soft gel capsules which found higher rates of diarrhoea in patients on once daily treatment.

The incidence of other side-effects was equal between patients, and there were no statistically significant differences in cholesterol or triglycerides between patients taking Kaletra once a day and those taking the drug twice a day.

No significant safety differences were seen in the first eight weeks of the study between the patients taking the tablet and soft gel formulations. Patients who switched to the tablet overwhelmingly said they preferred it.

“No clinically important differences were identified in the safety and tolerability of [once-daily] vs. [twice-daily] dosing of lopinavir/ritonavir”, write the investigators.


Gathe J et al. Study M05-730 primary efficacy results at week 48: phase 3, randomized, open-label study of lopinavir/ritonavir tablets once daily versus twice daily, co-administered with tenofovir DF and emtricitabine in antiretroviral-naïve HIV-1 infected subjects. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston. Poster 775, 2008.