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Rilpivirine vs Efavirenz for 96 Weeks: Baseline Viral Load and Side Effect Details
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13th European AIDS Conference, October 12-15, 2011, Belgrade
Mark Mascolini
Rilpivirine proved virologically noninferior to efavirenz through 96 weeks when either nonnucleoside was combined with tenofovir/emtricitabine in the ECHO and THRIVE studies [1]. Among people starting treatment with a viral load above 100,000 copies, however, there were more virologic failures with rilpivirine than with efavirenz. By many measures rilpivirine had a significantly better toxicity profile than efavirenz.
In the United States and Canada, rilpivirine and efavirenz can be taken once daily in a single pill combined with tenofovir/emtricitabine. The rilpivirine 3-in-1 pill, called Complera in the United States, is about 26% smaller than the efavirenz 3-in-1 pill, Atripla. Because of similar overall antiviral activity and convenience with these one-pill regimens, it is important to define advantages one agent may have over the other. Toward that end, ECHO [2] and THRIVE [3] investigators pooled results of those two phase 3 randomized trials to compare responses and outcomes after 96 weeks of treatment with rilpivirine versus efavirenz [1].
Both ECHO and THRIVE recruited antiretroviral-naive people from around the world and randomized them to rilpivirine or efavirenz plus two nucleos(t)ides. The trials differed in only one way: in ECHO everyone took tenofovir/emtricitabine with their nonnucleoside, while THRIVE participants could take tenofovir/emtricitabine, abacavir/lamivudine, or zidovudine/lamivudine. This 96-week pooled analysis included only people who took tenofovir/emtricitabine with their assigned nonnucleoside--690 people from ECHO and 406 from THRIVE.
People assigned to rilpivirine versus efavirenz did not differ in proportion of women (22% and 21%), median age (36 and 36), or proportions of whites, blacks, Asians, and Hispanics (64%, 24%, 10%, and 24% with rilpivirine and 61%, 23%, 13%, and 27% with efavirenz). Median pretreatment viral load was 100,000 copies in both treatment arms, median CD4 count stood at 247 in the rilpivirine group and 261 in the efavirenz group, and one third in each group started treatment with a CD4 count under 200.
In a time-to-loss-of-virologic response (TLOVR) analysis at 96 weeks, 77% in both treatment groups had a viral load below 50 copies, a result confirming that rilpivirine plus tenofovir/emtricitabine is noninferior to efavirenz plus tenofovir/emtricitabine in previously untreated people.
The researchers also determined week-96 virologic response by a so-called snapshot analysis, which used the last viral load between week 90 and week 103. In these analyses, rilpivirine was noninferior to efavirenz in subgroups who started treatment with a viral load below 100,000 copies (83% and 80% under 50 copies) or a viral load between 100,000 and 500,000 copies/mL (74% and 73% below 50 copies). But among people starting treatment with more than 500,000 copies, 60% taking rilpivirine and 75% taking efavirenz had a week-96 viral load below 50 copies (difference -14.6, 95% confidence interval -31.0 to 1.8).
All of the following results involve people who began treatment with more than 100,000 copies: A snapshot analysis figured a 22.1% virologic failure rate in the rilpivirine arm versus an 11.7% virologic failure rate in the efavirenz arm. Week-96 rates of virologic failure leading to discontinuation were 11.8% with rilpivirine and 3.8% with efavirenz. Proportions who discontinued treatment by week 96 for reasons other than a last viral load above 50 copies were 6.1% with rilpivirine and 3.4% with efavirenz. Among people with no viral load data in the 96-week snapshot window (weeks 90 to 103), proportions who discontinued treatment because of adverse events (such as side effects) or death were 3.1% in the rilpivirine arm and 10.7% in the efavirenz arm.
Adherence to treatment played a critical role in week-96 TLOVR response rates. ECHO and THRIVE investigators determined adherence by the Modified Medication Adherence Self-Report Inventory (M-MASRI) questionnaire, setting 95% as the cutoff for good adherence. Virologic response rates were always substantially lower in people with less than 95% adherence, though the adherence-determined response gap was smaller for efavirenz than for rilpivirine in people who began treatment with more than 100,000 copies:
Overall 96-week sub-50-copy TLOVR response rate:
Rilpivirine >95% adherence: 81%
Efavirenz >95% adherence: 83%
Rilpivirine < /=95% adherence: 56%
Efavirenz < /=95% adherence: 67%
96-week sub-50-copy TLOVR response rate with initial viral load
Rilpivirine >95% adherence: 87%
Efavirenz >95% adherence: 87%
Rilpivirine
Efavirenz
96-week sub-50-copy TLOVR response rate with initial viral load >100,000
Rilpivirine >95% adherence: 74%
Efavirenz >95% adherence: 80%
Rilpivirine < /=95% adherence: 50%
Efavirenz < /=95% adherence: 70%
In a resistance analysis, virologic failure rates after 1 year of follow-up were 11.5% in the rilpivirine arm and 4.2% in the efavirenz arm. In the second year of follow-up, rates of additional virologic failure were low with both rilpivirine (2.7%) and efavirenz (2.6%). In the rilpivirine arm there were 59 people with virologic failure and resistance data up to week 48 and 12 additional people up to week 96. In the efavirenz arm there were 18 people with virologic failure and resistance data up to week 48 and 12 additional people up to week 96. In these subgroups, rates of new nonnucleoside resistance mutations were similar in the rilpivirine group (58% at week 48 and 42% at week 96) and the efavirenz group (61% at week 48 and 33% at week 96). But rates of new nucleoside/nucleotide mutations were more frequent with rilpivirine failure (61% at week 48 and 42% at week 96) than with efavirenz failure (33% at week 48 and 17% at week 96).
Overall rates of any serious adverse event up to and beyond week 96 were similar with rilpivirine (9.5%) and efavirenz (11.2%). Grade 2 to 4 treatment-related adverse events were significantly less frequent with rilpivirine than efavirenz (17% versus 33%, P < 0.0001), as were rates of any treatment-related psychiatric adverse event (16% versus 27%, P < 0.0001) and rates of treatment-related rash (5% versus 16%, P < 0.0001). A significantly lower proportion discontinued rilpivirine than efavirenz by week 96 because of adverse events (4% versus 9%, P = 0.0011).
Grade 2 to 4 lab abnormalities were significantly less frequent with rilpivirine than efavirenz (50% versus 60%, P = 0.0007), as were grade 3 to 4 lab abnormalities (13% versus 21%, P = 0.0013). The most frequent lab abnormalities were hypophosphatemia (14% with rilpivirine, 15% with efavirenz), elevated pancreatic amylase (9% with rilpivirine, 10% with efavirenz), and hyperglycemia (8% with rilpivirine, 6% with efavirenz).
Week-96 changes in total cholesterol (+0.04 mmol/L with rilpivirine, +0.71 mmol/L with efavirenz), "bad" low-density lipoprotein cholesterol (-0.02 mmol/L with rilpivirine, +0.37 mmol/L with efavirenz), and triglycerides (-0.15 mmol/L with rilpivirine, +0.09 mmol/L with efavirenz) all favored rilpivirine. The efavirenz group gained more "good" high-density lipoprotein (HDL) cholesterol through week 96 (+0.09 mmol/L with rilpivirine, +0.28 mmol/L with efavirenz). The investigators did not report week-96 changes in total-to-HDL cholesterol ratio.
References
1. Nelson M, Behrens G, Cohen C, et al. Sustained efficacy with low and similar rates of virologic failures in second year observed with rilpivirine versus efavirenz plus emtricitabine/tenofovir DF in treatment-naive, HIV-1 infected adults--pooled 96-week ECHO and THRIVE analysis. 13th European AIDS Conference. October 12-15, 2011. Belgrade. Abstract LBPE7.3/7.
2. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378:238-246.
3. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378:229-237.
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