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The one-pill, once-daily fixed-dose combination of efavirenz with tenofovir/FTC (Atripla) has revolutionized the treatment of HIV infection in antiretroviral-naive patients. However, efavirenz is associated with neuropsychiatric adverse effects, rash, and lipid abnormalities and is contraindicated in pregnant women because of teratogenicity. In the ECHO and THRIVE trials, researchers evaluated whether rilpivirine, a recently approved novel once-daily nonnucleoside reverse transcriptase inhibitor (NNRTI), might be a reasonable alternative to efavirenz. Both studies were sponsored by the maker of rilpivirine. The results have previously been presented as pooled analyses but were published separately; here, we report them combined.
A total of 1368 treatment-naive patients were randomized to receive 25 mg of rilpivirine once daily (n=686) or 600 mg of efavirenz once daily (n=682), each in combination with two nucleoside reverse transcriptase inhibitors (NRTIs; 80% tenofovir/FTC, 15% AZT/3TC, 5% abacavir/3TC). At 48 weeks, treatment success (defined as a viral load <50 copies/mL without any treatment-limiting adverse events) was documented in 84% of the rilpivirine group and 82% of the efavirenz group, a nonsignificant difference. Rilpivirine was better tolerated than efavirenz, with fewer patients experiencing grade 2–4 adverse events (16% vs. 31%). In the efavirenz group, the main reason for treatment failure was adverse events, whereas in the rilpivirine group, it was virologic failure. Rilpivirine was associated with almost twice as many virologic failures as efavirenz (9% vs. 5%).
Forty-two patients with treatment failure on rilpivirine developed treatment-emergent NRTI mutations, and 39 developed new NNRTI mutations, 28 of which were E138K (known to confer resistance to all available NNRTIs, including etravirine). Of the patients with failure on efavirenz, 9 developed new NRTI resistance mutations, and 15 had new NNRTI mutations (no E138K). QT prolongation was clinically irrelevant and similar between groups.
Molina J-M 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 Jul 16; 378:238.
Cohen CJ 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 Jul 16; 378:229.
Schrijvers R et al. Rilpivirine: A step forward in tailored HIV treatment. Lancet 2011 Jul 16; 378:201.
Comment
Although rilpivirine and efavirenz led to similar rates of overall treatment success at 48 weeks (84% and 82%), important differences emerged: Rilpivirine had a much better safety profile than efavirenz, but it was also associated with more virologic failures. These results also held true in the 96-week analysis presented at the 2011 IAS Conference on HIV Pathogenesis, Treatment and Prevention (Abstract TULBPE032). Unfortunately, virologic failure with resistance development has more serious, longer-lasting clinical implications than treatment failure that is due to reversible adverse drug effects. Additional data presented at recent conferences indicate that the difference in the rate of virologic failure between the rilpivirine and efavirenz groups was most pronounced in patients with a baseline viral load >100,000 copies/mL (17% vs. 7%) — and that rilpivirine failure was strongly associated with incomplete adherence, especially in patients with high baseline viral loads (Abstract 9 at the 2011 International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies; Abstract H-1810 at the 2010 International Conference on Antimicrobial Agents and Chemotherapy).
Notably, the trial investigators had initially planned to use a 75-mg dose of rilpivirine but switched to the 25-mg dose after early phase II studies showed that higher doses caused prolongation of the QT interval. Given that a formal comparative QT study was never conducted, we are left to wonder whether a good drug could have been great if it had been dosed higher.
From a clinical perspective, rilpivirine-based regimens may be a reasonable option for patients who cannot tolerate — or who have contraindications to — tenofovir/FTC/efavirenz, especially those with excellent adherence and viral loads <100,000 copies/mL. A one-pill, once-daily fixed-dose combination of tenofovir/FTC/rilpivirine, dubbed “B-tripla” in the lay press, is currently being evaluated.