Once- vs. Twice-Daily Kaletra Tablets: Similar Safety and Potency
by Tim Horn
Once- and twice-daily doses of Kaletra (lopinavir/ritonavir) tablets have similar tolerability and comparable efficacy, according to 48-week results from a clinical trial reported yesterday at the 15th Conference on Retroviruses and Opportunistic Infections (CROI).
In the United States, Kaletra has been approved by the U.S. Food and Drug Administration (FDA) for use once or twice daily in people starting HIV treatment for the first time, with a total daily dose of 800 mg lopinavir and 200 mg ritonavir using either schedule. Only twice-daily dosing is approved for treatment-experienced patients.
Despite approval from the FDA, there have been lingering concerns about the safety and effectiveness of once-daily Kaletra therapy in treatment-naive patients.
Initial studies comparing once- and twice-daily Kaletra involved the original capsule formulation of the drug. While the effectiveness of once-daily Kaletra was found to be comparable to twice-daily dosing, diarrhea rates were higher in the once-daily group.
Abbott eventually brought a tablet version of the drug to market that, according to a study of patient surveys in October 2006, was less likely to cause diarrhea.
Questions soon emerged about the effectiveness of the drug taken once daily, notably in patients starting therapy for the first time with high viral loads (100,000 copies or higher). This was explored, in some detail, in two presentations at the 11th European AIDS Conference this past October in Madrid.
While Kaletra remains a “preferred” protease inhibitor for HIV-positive individuals starting therapy for the first time, the U.S. Department of Health and Human Service’s most recent version of its federal treatment guidelines—updated January 29, 2008—suggests that twice-daily Kaletra may be a more suitable dosing option for those with high pre-treatment viral loads.
To better understand the safety and efficacy of once- and twice-daily dosing of the Kaletra tablets—and to formally compare Kaletra tablets with Kaletra capsules—Abbott funded an international study involving 600 HIV-positive patients beginning antiretroviral therapy for the first time. For the first eight weeks of the study, the patients were divided into four groups: one group took twice-daily Kaletra tablets, a second group took twice-daily Kaletra capsules, a third group took once-daily Kalera tablets, and a fourth group took once-daily Kaletra capsules. From there, patients in the once-daily Kaletra groups were maintained on once-daily Kaletra tablets; patients in the twice-daily Kaletra groups continued the study using twice-daily Kaletra tablets.
All patients received standard doses of Viread (tenofovir) and Emtriva (emtricitabine) throughout the study.
According to Joe Gathe, MD, a Houston-based researcher who presented the results of Study M05-730 at CROI, approximately 78 percent of the study volunteers were male and roughly 75 percent were white. Average viral loads at the start of the study were almost 100,000 copies, with an even distribution of patients with viral loads below and above this level. CD4 counts at baseline averaged 215 cells.
In the comparison between Kaletra capsules and tablets, no significant differences in the side effects of the two formulations were reported—rates of mild-to-severe diarrhea were similar in all four groups of patients during the first eight weeks of the study.
As for the the comparison between once- and twice-daily Kaletra tablets—the predominant focus of the CROI presentation—77 percent in the once-daily Kaletra group and 76 percent in the twice-daily Kaletra group had viral loads below 50 copies after 48 weeks. As this difference was so slight, the once-daily results were said to be “non-inferior” to the twice-daily findings—comparable efficacy between the two groups.
There were no statistically significant differences in treatment responses between the two groups among those who entered with viral loads above or below 100,000. Similarly, there were no statistically significant differences in the virologic response to once- or twice-daily Kaletra treatment among those who entered with CD4 counts below 50 cells, between 50 and 200 cells, or above 200 cells.
Seven patients had resistance testing available—10 in the once-daily group and seven in the twice-daily group—through week 48. No resistance to lopinavir or tenofovir was documented. Three—two in the once-daily group and one in the twice-daily group—had HIV that developed the M184V mutation, conferring high-level resistance to Emtriva.
As for side effects, rates of moderate or severe diarrhea were similar between the two groups, occurring in 17 percent of those in the once-daily Kaletra group and 15 percent of those in the twice-daily Kaletra group. Moderate or severe nausea occurred in 7 and 5 percent and vomiting in 3 and 4 percent, respectively.
Moderate or severe lab abnormalities, such as liver enzyme increases, cholesterol gains, triglyceride elevations and decreases in creatinine clearance, generally occurred in less than 5 percent of the patients enrolled in the clinical trial, with no statistically significant differences between the two study groups.
The only statistically significant difference between the two groups was the change in total cholesterol after 48 weeks of treatment: a gain of 29 mg/dL in the once-daily Kaletra group, compared with a 34.5 mg/dL gain in the twice-daily Kaletra group.
Finally, Dr. Gathe ad his colleagues explained that study volunteers who switched from Kaletra capsules to tablets after the first eight weeks of the study, “overwhelmingly preferred” the tablets to the capsules.
The researchers concluded, “This study is the largest study to date comparing once-daily and twice-daily dosing of Kaletra, and the first utilizing the tablet formulation. Overall, during the first 48 weeks of treatment, no clinically important differences were identified in the safety and tolerability of once-daily vs. twice-daily dosing of Kaletra.”
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LEE ANN CORRALES, Atlanta, 2008-02-13 00:41:19
I have been taking Kaletra tables for over two years. I take all four tablets at one time with no side effects. My viral load has remained undectable and my cd 4 has remained between 900 and 1,000. I am very happy with Kaletra and hope to continue to take it with no side effects.
