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HIV Drug Therapy: Lower-dose Efavirenz Equally Effective with Fewer Side Effects

A reduced dose of efavirenz (Sustiva or Stocrin) for first-line HIV therapy suppressed viral load as well as the standard dose, but was associated with fewer characteristic side effects, researchers reported at the recent HIV Drug Therapy 2014 meeting in Glasgow. A related study found that half the dose maintained viral suppression in people with high efavirenz levels in their blood.

Efavirenz is a generally safe and highly effective component of antiretroviral therapy (ART), but it commonly causes neuropsychiatric side effects including dizziness, insomnia, abnormal dreams, and anxiety. Using a lower dose may reduce adverse effects and could also treatment decrease cost in resource-limited settings.

First-line Therapy

Dianne Carey from the Kirby Institute in Sydney and fellow investigators with the ENCORE 1 Study Group compared the efficacy and safety of reduced versus standard doses of efavirenz for first-line HIV therapy.

This multinational non-inferiority trial enrolled more than 600 treatment-naive people with HIV in 13 countries in Europe, Africa, the Asia-Pacific region, and Latin America. About two-thirds were men and the mean age was 36 years. Caucasians, Africans, and Asians each accounted for approximately one-third of participants. The average CD4 T-cell count was low, at 99 cells/mm³, and one-third had high viral load at baseline (>100,000 copies/mL).

Participants were randomly assigned to receive a reduced dose of 400 mg or the standard dose of 600 mg once-daily efavirenz plus tenofovir/emtricitabine (the drugs in Truvada).

Results from the primary analysis at 48 weeks were previously reported at the 2013 International AIDS Society Conference. Carey reported results from continued follow-up through 96 weeks. A total of 585 participants completed 96 weeks of randomized treatment.

Results

• As previously reported, the 48-week primary analysis showed that 400 mg efavirenz was non-inferior to 600 mg.
• At 96 weeks, 90.0% of participants receiving the 400 mg dose and 90.6% receiving the 600 mg dose had HIV RNA <200 copies/mL in an intent-to-treat analysis.
• The difference of 0.6% fell within the predefined margin of 10%, showing that 400 mg efavirenz remained non-inferior to 600 mg at 96 weeks.
• Efavirenz was also non-inferior when using lower (<50 copies/mL) and higher (<400 copies/mL) viral load cut-offs, and for people with either high or low baseline viral load.
• The mean CD4 cell gain was 25 cells/mm³ greater in the 400 mg compared with the 600 mg arm, a difference that reached statistical significance but which Carey said was not likely to be clinically meaningful.
• Both efavirenz doses were generally safe and well-tolerated.
• There was no significant difference in the frequency or severity of overall adverse events, or of serious adverse events, in the 2 dose arms.
• However, people taking the 400 mg dose reported significantly fewer adverse events that were considered definitely or probably efavirenz-related (38% vs 48%, respectively).
• Fewer people stopped treatment early due to side effects in the lower-dose group (8% vs 23%, respectively), though the difference did not reach statistical significance.

"Non-inferiority of efavirenz 400 mg to efavirenz 600 mg when combined with [tenofovir/emtricitabine] as initial HIV therapy was confirmed at week 96," the researchers concluded. "These results support the use of a lower efavirenz dose as part of routine HIV management."

Maintenance Therapy

In a related study, Chien-Ching Hung, Shang-Ping Yang, and colleagues from National Taiwan University evaluated the effectiveness of a reduced dose of efavirenz plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) as maintenance therapy after achieving viral suppression. Dose reduction was done with the guidance of therapeutic drug monitoring.

Plasma efavirenz concentrations have been shown to vary widely from person to person, and a substantial proportion of patients therefore may have unnecessarily high concentrations when taking the standard 600 mg dose.

This open-label study enrolled Taiwanese HIV patients starting in April 2013. Most (94%) were men and the mean age was 39 years. Almost all had HIV RNA <200 copies/mL at baseline. The researchers tested for CYP2B6 G516T polymorphisms, a genetic variation in an enzyme that metabolizes efavirenz.

Plasma efavirenz concentrations were measured 12 hours after taking the previous dose. A total of 157 participants with levels above 2.0 mg/L cut their dose to from a whole tablet (600 mg) to half a tablet (300 mg) once-daily. Efavirenz levels were measured again 4-12 weeks after dose reduction.

Among patients who qualified for dose reduction, 42% had CYP2B6 G516T gene variants associated with higher efavirenz concentrations and 32% weighed 60 kg (132 lb) or less.

At 3 months after dose reduction, 98.6% of participants had undetectable viral load (<50 copies/mL) -- about the same as the proportion at baseline. Before dose reduction, the mean efavirenz concentration was 3.43 mg/L at 12 hours after the last dose, falling to 1.74 mg/L after halving the dose. About 80% of patients with efavirenz-related adverse events at baseline reported improvement after lowering their dose.

Switching to combination ART containing a half tablet of efavirenz in patients with higher plasma concentrations who had achieved viral suppression "could maintain successful viral suppression with the guidance of therapeutic drug monitoring," the investigators concluded.

12/23/14

References

D Carey. Efavirenz 400 mg daily remains non-inferior to 600 mg: 96 week data from the double-blind, placebo-controlled ENCORE1 study. HIV Drug Therapy Glasgow Congress 2014. Glasgow, November 2-6, 2014. Abstract O421.

S-P Yang, W-C Liu, K-Y Lee, et al. Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring. HIV Drug Therapy Glasgow Congress 2014. Glasgow, November 2-6, 2014. Abstract O422.