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Once- and Twice-Daily Lopinavir/Ritonavir Equivalent in Antiretroviral Experienced
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
After 48 weeks in a randomized trial that enrolled people taking a failing regimen, viral load, CD4 count, and safety profiles were similar with once-daily lopinavir/ritonavir and the twice-daily dose [1]. Once-daily lopinavir/ritonavir is licensed for people starting their first antiretroviral regimen, but not yet for people with antiretroviral experience. Earlier research established the equivalence of once-daily dosing and twice-daily dosing in previously untreated people [2].
In this nonblinded trial, investigators in Argentina, Brazil, Mexico, South Africa, and the United States randomized 599 antiretroviral-experienced patients to switch to once-daily lopinavir/ritonavir (800/200 mg) or to twice-daily dosing (400/100 mg) plus two or more nucleosides. Individual investigators picked nucleosides based on resistance test results. Although about 15% of study participants had never taken a nonnucleoside, drugs in this class were not allowed in the trial. Drugs from newer antiretroviral classes were not allowed either.
No one had taken lopinavir before, and everyone took lopinavir/ritonavir tablets. Everyone had a starting viral load above 1000, and enrollees could have any CD4 count. The primary endpoint was the proportion of people with a viral load below 50 copies/mL at week 48 by the FDA-favored analysis, time-to-loss-of-virologic response (TLOVR).
When the study began, viral load averaged 20,000 copies, while starting CD4 counts averaged 254. People in the twice-daily arm had a significantly higher average CD4 count (268 versus 239, P = 0.047), but that difference is probably not clinically meaningful. About half of the study participants in each arm had PI experience, and they averaged 1.2 PI mutations (range 0 to 7). Race and ethnicity proportions were similar in the two treatment arms, with 49% nonwhite. One third of study enrollees were women.
Just over three quarters of each treatment group completed the study, with virtually no difference between the once-daily group (78%) and the twice-daily group (77%). While 4.7% in the once-daily group dropped out because of side effects, 7.4% in the twice-daily group quit for that reason, but the difference lacked statistical significance. Thirteen people (4.3%) left the once-daily arm because of poor adherence, compared with 17 (5.7%) in the twice-daily arm.
There were 12 virologic failures with once-daily lopinavir/ritonavir (4.9%) and 10 with twice-daily dosing (3.3%). In the primary TLOVR analysis after 48 weeks, 55% in the once-daily arm and 52% in the twice-daily arm had a viral load under 50 copies, a result establishing that once-daily dosing is not inferior to twice-daily dosing in people with antiretroviral experience. The 95% confidence interval for the difference was -4.5% to 11.5%, well within the preset noninferiority margin of -12%. In an on-treatment analysis, 76% taking lopinavir/ritonavir once-daily and 72% taking it twice daily had a week-48 viral load under 50 copies, a nonsignificant difference. The investigators did not analyze responses in people with viral loads above or below 100,000 copies at entry.
In people with 0, 1, or 2 PI mutations when they entered the study, equivalent proportions in the two groups at a viral load under 50 copies at week 48. Among people with 3 or more pretreatment PI mutations, substantially fewer taking the once-daily dose had a sub-50 load at week 48:
· <50 with 0 mutations: 74/105 (70.5%) once daily, 62/98 (63.3%) twice daily
· <50 with 1 mutation: 67/107 (62.6%) once daily, 62/106 (58.5%) twice daily
· <50 with 2 mutations: 26/43 (60.5%) once daily, 30/46 (65.2%) twice daily
· <50 with 3 or more mutations: 4/13 (30.8%) once daily, 8/14 (57.1%) twice daily
Whether the difference with 3 or more PI mutations suggests a response cutoff is open to question. The investigators argued that they could not draw a conclusion on that point because of the small number of people with that many PI mutations.
Average CD4 gains through 48 weeks were similar with both regimens: 133 once daily and 119 twice daily.
A significantly lower proportion of people taking lopinavir/ritonavir once daily complained of nausea (3% versus 7% twice daily, P = 0.009). Diarrhea rates were similar with either dosing strategy (14% once daily and 11% twice daily).
Triglyceride and cholesterol levels did not differ with the two dosing regimens.
David Cooper (University of New South Wales), who was not involved in the trial, suggested that TLOVR response rates in the low 50% range are less than one would hope for with a rescue regimen given to people with relatively limited antiretroviral experience. But Sharlaa Badal-Faesen (University of Witwatersrand) said the investigators were not surprised with this result, which they rated as similar to findings in earlier lopinavir/ritonavir trials that enrolled experienced people, such as TITAN.
References
1. Zajdenverg R, Badal-Faesen S, Andrade-Villanueva J, et al. Lopinavir/ritonavir tablets administered once- or twice-daily with NRTIs in antiretroviral-experienced HIV-1 infected subjects: results of a 48-week randomized trial (Study M06-802). 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB104.
2. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses. 2007;23:1505-1514.
3. Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370:49-58.
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