The first head-to-head comparison of the two most frequently recommended first-line regimens has found that the combination of two nucleosides plus efavirenz (Sustiva) may be more durable over two years than combining two nucleosides with ritonavir-boosted lopinavir (Kaletra), although the reasons for this are unclear. The surprising results were presented during Thursday's late-breaker session at the Sixteenth International AIDS Conference in Toronto. The study, conducted by the US-government funded AIDS Clinical Trial Group (ACTG), also found that a nucleoside-sparing regimen that combined efavirenz with Kaletra was almost as effective as efavirenz-based triple therapy.
Current treatment guidelines for high-income countries, including the United States and the United Kingdom, recommend that first-line therapy should contain two nucleosides and either one non-nucleoside (NNRTI) or a boosted protease inhibitor (PI). The NNRTI, efavirenz, and the boosted PI, Kaletra, are the favoured choices, and consequently these two drugs are the most frequently prescribed in their respective classes.
Until now, there had been no large-scale randomised clinical trials comparing the two regimens, although there has been a perception amongst some physicians that Kaletra was more potent for people initiating therapy with viral loads greater than 100,000 copies/ml, and that it was possibly more durable than efavirenz, based on longer clinical experience as well as four year follow-up data in a small group of individuals from the drug's manufacturer, Abbott.
In the study presented in Toronto today, 753 HIV-positive individuals starting antiretroviral therapy for the first time at 55 sites throughout the United States were randomised in an open-label, prospective trial to one of three treatment arms. The study's primary objectives were to compare the time to virologic failure (defined as HIV viral load above 200 copies/ml after week 32) and regimen completion (defined as discontinuation due to either virological failure or toxicity of any regimen component).
A total of 250 individuals were assigned efavirenz-based (600mg once daily) triple-drug therapy that included two nucleosides. Another 253 received the old soft-gel formulation of Kaletra (400mg lopinavir/100mg ritonavir twice daily) alongside two nucleosides. Participants in the triple-drug therapy groups also received 3TC (lamivudine, Epivir), plus their choice of AZT (zidovudine, Retrovir; 42%), d4T (stavudine, Zerit; 24%), or tenofovir (Viread; 34%).
The remaining 250 individuals received a two drug nucleoside-sparing regimen consisting of efavirenz and Kaletra.
At the start of the study, the median viral load was approximately 100,000 copies/ml and the median CD4 cell count was 182 cells/mm3, suggesting that the study population had relatively advanced HIV disease, and were starting treatment somewhat later than current guidelines recommend.
The investigators found that all three treatment regimens were potent, with substantial CD4 cell increases and viral load decreases after 96 weeks.
Analysis of the primary endpoint, time to virologic failure, showed:
- No significant difference in time to failure by Kaplan-Meier analysis between the Kaletra and Kaletra/efavirenz arms (p=0.13), or between the Kaletra/efavirenz and efavirenz arms (p=0.5).
- A signficant difference in time to virologic failure between the Kaletra arm and the efavirenz arm (p=0.006)
Secondary endpoint analyses highlighted further differences between the regimens. In particular, in intent-to-treat analysis, 89% of the participants receiving efavirenz-based triple therapy had viral loads below 50 copies/ml after 96 weeks, compared with 77% receiving Kaletra-based triple therapy (p=0.003). In addition, 83% of the participants on the nucleoside-sparing regimen had viral loads below 50 copies/ml after 96 weeks (a non-significant difference with the two other arms).
On the other hand, CD4 cell count increases appeared to be greater in the two study arms containing Kaletra. After 96 weeks, median CD4 cell counts increased from baseline by 285 cells/mm3 in those receiving Kaletra-based triple therapy, and by 268 cells/mm3 in the participants on the nucleoside-sparing regimen, compared with the efavirenz-based triple regimen (with an increase of 241 cells/mm3; both differences p=0.01).
The researchers were unclear why fewer participants on Kaletra-based triple therapy achieved viral loads below 50 copies/ml at week 96, compared with those on efavirenz-based triple therapy, since they found that the time to treatment-limiting toxicity was similar for all arms, and the proportion of grade 3 or 4 clinical adverse events was similar in each arm, at around 20%. A larger proportion of patients in the Kaletra plus efavirenz arm experienced grade 3 or 4 laboratory toxicities (45% vs 33% for Kaletra and 32% for efavirenz), although the presenter, Dr Sharon Riddler of the University of Pittsburgh, did not state whether this difference was significant. The difference appeared to be driven by elevations in triglycerides and LDL cholesterol, both of which are known metabolic complications associated with Kaletra therapy.
"It may be that the lopinavir/ritonavir regimen, which was dosed twice daily using the soft gel capsule form, was less convenient or less well tolerated by patients," co-author Dr Richard Haubrich said in an accompanying press release, adding that they will continue to evaluate their study data to try to assess the reasons for their findings.
In addition, although a small, open-label pilot study from France published in the journal AIDS last year found that 69% of mostly treatment-naive individuals taking the nucleoside-sparing regimen of efavirenz and Kaletra achieved viral loads below 50 copies/ml after 48 weeks, this dual combination had not been studied in larger-scale trials, and is not currently recommended in treatment guidelines.
Dr Sharon Riddler, presenting, asserted that since "we found that the NRTI-sparing two-drug combination of efavirenz and lopinavir had a similar level of effectiveness to the efavirenz plus two-NRTI regimen...there should be little doubt that patients can benefit from this 'nuke'-sparing treatment regimen when NRTI side-effects are a problem."
However the preliminary resistance analysis showed that patients experiencing virological failure in the Kaletra / efavirenz arm showed a trend towards a higher rate of NNRTI resistance when compared with the efavirenz arm (69% vs 48% among those virologic failures who underwent genotypic testing). Resistance mutations in two drug classes - NRTI-associated (M184V) and NNRTI-associated (K103N) - were more common in the efavirenz group plus NRTIs group than in Kaletra-treated patients, and primary protease inhibitor mutations were detected in only two of 91 patients who failed a Kaletra-containing regimen.
Riddler SA et al. A prospective, randomized, Phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection - ACTG 5142. Sixteenth International AIDS Conference, Toronto, abstract ThLB0204, 2006.