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Higher CD4 Gains With 2nd-Line Regimen Excluding NRTIs in Randomized Trial
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
A second-line regimen combining lopinavir/ritonavir with raltegravir pushed CD4 counts significantly higher than lopinavir with two or three nucleoside reverse transcriptase inhibitors (NRTIs) in the 48-week international SECOND-LINE Study [1]. The two second-line regimens proved similar in virologic efficacy through 48 weeks in this randomized, open-label trial.
Second-line antiretroviral planning has rested largely on reason, resistance testing, and intuition--but on scant randomized trial data. That will change after the 20th Conference on Retroviruses, which showcased two randomized trials of second-line therapy. The ACTG OPTIONS trial [2], reviewed separately by NATAP, found individually tailored NRTI-sparing regimens noninferior to standard NRTI-containing regimens after 48 weeks, and similar in impact on CD4 counts. The SECOND-LINE trial took a different approach, looking only at people in whom a first-line nonnucleoside was failing and specifying that the NRTI-sparing regimen must be lopinavir/ritonavir plus the integrase inhibitor raltegravir [1].
SECOND-LINE enrolled adults with two viral loads above 500 copies while taking a nonnucleoside-based regimen and naive to protease inhibitors and integrase inhibitors [3]. Enrollees had to take their nonnucleoside regimen for at least 24 weeks, with no changes in the 12 weeks before trial screening. Genotyping to help select second-line NRTIs was optional; sites without genotyping used an algorithm to pick second-line NRTIs. Primary endpoints were a viral load below 200 copies after 48 weeks in a modified intention-to-treat (mITT) population, a per-protocol population, and a noncompleter-equals-failure (FDA snapshot) population.
Participants came from multiple sites in 17 countries--Argentina, Australia, Chile, France, Germany, Hong Kong, India, Ireland, Malaysia, Mexico, New Zealand, Nigeria, Peru, Singapore, South Africa, Taiwan, and the United Kingdom. Study sponsors were the Kirby Institute in Sydney, amFAR, Abbott, and Merck (makers of lopinavir and raltegravir). The trial excluded anyone with active HBV infection, uncontrolled opportunistic infection, or current alcohol or illicit substance use.
SECOND-LINE investigators randomized 271 people to lopinavir and two or three NRTIs and 270 to lopinavir plus raltegravir. Participants in the two arms were similar in age (average 38.5), and proportions of men (55.1%), Asians (42.3%), Africans (36.0%), Hispanics (13.9%), and Caucasians (7.6%). Heterosexual intercourse was the primary HIV transmission mode (72.8%).
Estimated durations of HIV infection and NNRTI therapy were 6.0 and 3.5 years. Despite this long treatment duration, CD4 counts averaged only 190, with little difference between arms. About 60% had a viral load above 10,000 copies, with little difference between arms, which suggests many participants were taking a failing regimen for some time. But without genotyping at all study sites, there is no way to tell how many study participants may have taken compromised second-line NRTIs.
Numbers of participants reaching week 48 on therapy were 232 (86%) in the NRTI group and 241 (89%) in the raltegravir group. At week 48 proportions with a viral load below 200 copies in the mITT population were 80.8% with NRTIs and 82.6% with raltegravir (P = 0.59). Among people with a baseline viral load above 100,000 copies, week 48 sub-200 response rates were 59.6% with NRTIs and 65.0% with raltegravir, still a nonsignificant difference (P = 0.56).
Proportions with a viral load below 50 copies were 70.5% with NRTIs and 71.1% with raltegravir in the mITT population, 73.5% and 75.2% in the per-protocol population, and 66.4% and 68.2% in the noncompleter population. None of these differences approached statistical significance.
In the ACTG OPTIONS trials, individually constructed NRTI-sparing regimens--most including raltegravir--were virologically noninferior to NRTI-containing regimens at 48 weeks [2], though the designs and populations of these two second-line trials differed greatly.
CD4 counts rose by an average 132.5 in the NRTI arm and 167.5 in the raltegravir arm, a significant difference (P < 0.01). Given the low baseline CD4 counts in this population, that difference may seem clinically meaningful. But rates of AIDS events and serious non-AIDS events did not differ between arms. Neutrophils rose slightly but significantly more with the raltegravir regimen (0.9 versus 0.7 cells/mm(3), P = 0.05), and there was a trend toward greater hemoglobin gains with raltegravir (6.1 versus 3.7 g/L, P = 0.07).
Total, LDL, and HDL cholesterol all rose significantly more with raltegravir than NRTIs, but changes from baseline in total-to-HDL ratio were similar in the two arms. The regimens did not differ in their impact on triglycerides, estimated glomerular filtration rate, creatine kinase, glucose, insulin, or insulin resistance.
Eight people in the NRTI arm and 4 in the raltegravir arm died, but mortality (2.2 and 1.0 per 100 person-years) did not differ significantly between arms. There was a trend to a higher adverse event rate per 100 person-years in the NRTI arm (410.7 versus 362.9, P = 0.09). Rates of serious adverse events did not differ significantly between study arms.
SECOND-LINE investigators concluded that their findings support World Health Organization advice to combine lopinavir/ritonavir with NRTIs after first-line nonnucleoside failure. They also suggested their results provide "robust support for an alternative strategy of switching to lopinavir/ritonavir plus raltegravir." Simplicity is one advantage of lopinavir/ritonavir plus raltegravir, they observed, although it does require twice-daily dosing. For low- and middle-income countries--and some high-income countries--costs also remain a critical factor in planning second-line therapy.
References
1. Boyd M, SECOND-LINE Study Team. SECOND-LINE: Ritonavir-boosted lopinavir with 2-3N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 180LB. http://www.retroconference.org/2013b/PDFs/180LB.pdf
2. Tashima K, Smeaton L, Andrade A, et al. Omitting NRTI from ARV regimens is not inferior to adding NRTI in treatment-experienced HIV+ subjects failing a protease inhibitor regimen: the ACTG OPTIONS study. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 153LB.
3. ClinicalTrials.gov. A trial of 2 options for second line combination antiretroviral therapy following virological failure of a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)+2N(t)RTI first line regimen (SECOND-LINE). http://www.clinicaltrials.gov/ct2/show/NCT00931463?term=second-line&rank=1
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