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First-Line Lopinavir/r/Raltegravir (With No NRTIs) in Treatment Naive
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XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
A two-drug first-line regimen combining raltegravir with lopinavir/ritonavir controlled HIV as well as a standard triple regimen, lopinavir/ritonavir plus tenofovir/emtricitabine (TDF/FTC) after 48 weeks in the randomized PROGRESS trial [1]. CD4 gains through 48 weeks were moderately lower with raltegravir than with TDF/FTC, but that difference was not statistically significance. Low initial viral loads among study participants present a possible caution to applying these results to treatment-naive people with more advanced HIV infection (from Jules: The average baseline viral load for the study was a low 4.2 logs so a question was asked from the audience was the response the same regardless of baseline viral load).
Development of antiretrovirals with new mechanisms, including the CCR5 antagonist maraviroc and the integrase inhibitor raltegravir, has prompted clinical investigators to test two-drug regimens for previously untreated people to see how they compare with classic three-drug combos including a ritonavir-boosted protease inhibitor or efavirenz plus two nucleosides. In this ongoing, 96-week, open-label trial, PROGRESS investigators randomized 101 antiretroviral-naive people to raltegravir (400 mg twice daily) and 105 to TDF/FTC (300/200 mg once daily), each with lopinavir/ritonavir (400/100 mg twice daily).
All study participants had a viral load above 1000, and any CD4 count was allowed. Study entry variables were similar in the two study groups. Pretreatment viral load averaged 4.25 log (about 18,000 copies, range 2.0 to 6.0 log), and pretreatment CD4 count averaged 293.5 (range 5 to 743). Most study participants (84.5%) were men, most (75.2%) were white, and participants' ages averaged 39.6 years (+/- 10.6).
Through the first 48 weeks, 8 people (8%) quit the raltegravir am and 11 (10.5%) dropped out of the TDF/FTC arm. Two people in each group left the trial because of an adverse event. One person in the raltegravir group and 2 in the TDF/FTC group stopped treatment because of virologic failure.
According to the FDA-favored time-to-loss-of-virologic-response method, 83% taking raltegravir and 85% taking TDF/FTC had a viral load below 40 copies at week 48. The 95% confidence interval for the difference (-12% to +8%) fell within the lower bound needed (at or above -20%) to establish that first-line lopinavir/raltegravir is noninferior to lopinavir/TDF/FTC.
Four people taking raltegravir and 3 taking TDF/FTC met protocol-defined criteria for resistance testing. The only mutation detectable with standard sequencing in the in the raltegravir group was a raltegravir-related mutation. The only detectable mutation in the TDF/FTC group was M184V, conferring resistance to FTC.
People taking raltegravir with lopinavir/ritonavir gained an average 215 CD4 cells through 48 weeks, compared with a 245-cell gain in the TDF/FTC group, but that difference was not statistically significant (P = 0.237).
Rates of moderate or severe side effects that emerged during treatment were similar in the two study arms. The most common were diarrhea (8% in the raltegravir group, 13% with TDF/FTC, P = 0.261) and high cholesterol (8% in the raltegravir group and 5% with TDF/FTC, P = 0.401).
The treatment arms differed in some lab abnormality rates. As might be expected, 4 people taking TDF/FTC versus 1 taking raltegravir had a calculated creatinine clearance below 50 mL/min. Seven taking TDF/FTC and 4 taking raltegravir had a lipase elevation more than 2 times the upper limit of normal. Alanine aminotrasferase more than 5 times the upper limit of normal was more common with raltegravir than TDF/FTC (3 patients versus 1), as were elevated aspartate aminotransferase (5 versus 1), elevated creatine phosphokinase (13 versus 4), calcium below 1.75 mmol/L (2 versus 0), and triglycerides above 8.475 mmol/L (10 versus 5).
After the presentation, clinical researcher Joseph Eron (who was not involved in the trial) noted the low starting viral load in this study group and wondered if the results can be readily applied to a broader population of antiretroviral-naive people.
Reference
1. Reynes J, Lawal A, Pulido F, et al. Lopinavir/ritonavir combined with raltegravir demonstrated similar antiviral efficacy and safety as lopinavir/ritonavir combined with tenofovir disoproxil fumarate/emtricitabine in treatment-naïve HIV-1 infected subjects. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract MOAB0101.
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