Once-daily etravirine does well in patients starting HIV therapy

First-line HIV therapy that includes a once-daily dose of the new NNRTI etravirine is just as likely to suppress viral load to undetectable levels as treatment based on efavirenz, a study published in the online edition of AIDS shows.

“There were similar rates of HIV RNA suppression…for patients taking etravirine 400 mg once daily and efavirenz once daily, both with two nucleoside analogues,” write the investigators.

The virologic failure of etravirine (Intelence) was rare, and did not involve resistance to drugs in either the non-nucleoside reverse transcriptase inhibitor (NNRTI) or nucleos(t)ide reverse transcriptase inhibitor (NRTI) classes.

Moreover, therapy with etravirine was less likely than treatment with efavirenz to cause neuropsychiatric side-effects and also had a friendlier lipid profile.

Antiretroviral treatment guidelines recommend that first-line therapy should include two NRTIs with either a NNRTI or boosted protease inhibitor. The favoured NNRTI is efavirenz (Sustiva), its once-daily dose being 600 mg.

Efavirenz is generally safe, but it can cause neuropsychiatric side-effects, especially during the early weeks of therapy. The drug has also been associated with increases in cholesterol.

Etravirine is a new NNRTI. Clinical trials involving treatment-experienced patients showed that a twice-daily 200 mg dose worked against virus with resistance to efavirenz and nevirapine (Viramune). 

There is also some evidence that etravirine works well when used in first-line HIV therapy and that it can be taken as a once-daily 400 mg dose. Therapy with etravirine also appears to involve a smaller risk of neuropsychiatric side-effects than efavirenz.

Investigators from the international SENSE study wanted to gain a better understanding of the safety and effectiveness of etravirine when the drug was taken once-daily by patients starting HIV therapy.

They therefore designed a phase 2 study involving 157 patients. They were randomised to receive either once-daily etravirine (n = 79), or once-daily efavirenz (n = 78). The NNRTI was taken with an NRTI backbone of either Truvada (FTC/tenofovir),  Kivexa (3TC/abacavir), or Combivir (3TC/AZT). None of the patients had a major resistance mutation.

Changes in viral load and CD4 cell count were monitored over 48 weeks. Patients experiencing virologic failure were tested for resistance to anti-HIV drugs.

Data were also gathered on neuropsychiatric side-effects (the primary aim of the study), the occurrence of rash, and lipid increases.

Most of the patients were white men and their mean age was 38 years.

Median baseline viral load was approximately 68,000 copies/ml, and median CD4 cell count on entry to the study was 302 cells/mm³. Just over a third of patients (34%) had a baseline viral load above 100,000 copies/ml.

One year after starting therapy, an intent-to-treat analysis showed that 76% of patients taking etravirine had an undetectable viral load compared to 74% of individuals treated with efavirenz.

The two drugs also appeared equally effective in patients whose baseline viral load was above 100,000 copies/ml. After 48-weeks of treatment, 74% if those taking etravirine had a viral load below 50 copies/ml compared to 67% of individuals taking efavirenz.

However, the trial was not sufficiently powered to prove the non-inferiority of etravirine compared to efavirenz. The investigators comment: “Clinical trials to demonstrate non-inferior rates of HIV suppression normally require from 300-400 patients per treatment arm.”

Four patients treated with etravirine had a detectable viral load at week 48. Three of these individuals had a viral load below 200 copies/ml. None developed resistance to either NNRTIs or NRTIs.

There were seven patients with virological failure at week 48 in the efavirenz arm, and three individuals developed a major resistance mutation.

Forty-eight week increases in CD4 cell count were similar for the two drugs (median, 230 cells/mm³).

The prevalence of neuropsychiatric side-effects peaked at week twelve of the study, when they were recorded in 14% of patients in the etravirine arm and 40% of patients treated with efavirenz (p < 0.001).

There was still a significance difference at week 48 between the two study arms in the prevalence of neuropsychiatric side-effects (6% vs. 22%, p = 0.01).

The percentage of patients with at least one grade 2-4 (moderate to severe) drug-related nervous side-effect was 1% in the etravirine arm and 17% in the efavirenz arm.

A total of 5% of the etravirine-treated patients had a grade 2-4 psychiatric side-effect compared to 15% of patients in the efavirenz arm (p < 0.05). The most commonly reported psychiatric side-effects in the efavirenz arm were sleep disorders.

Four patients in the efavirenz arm stopped therapy because of a nervous or psychiatric side-effect compared to none of those taking etravirine.

Skin rashes developed in 18 patients (nine in each study arm).

Grade 3 elevations in total cholesterol and LDL cholesterol occurred in 8% and 10% of the patients taking efavirenz. In contrast, few patients treated with etravirine experienced serious increases in their lipids.

“Etravirine showed a lower risk of neuropsychiatric adverse events and lipid elevations than efavirenz,” conclude the investigators, who add “both safety benefits were sustained though Week 48. There were similar rates of HIV RNA suppression in the two treatment arms, and none of the patients with virological failure in the etravirine arm developed resistance.”

Gazzard B et al. Phase 2 double-blind, randomised trial of etravirine versus efavirenz in treatment-naïve patients: 48 week results. AIDS, online edition, doi: 10.1097/QAD.0b013e32834c4c06, 2011 (click here for the free abstract).