Switching from Atripla to Eviplera reduces central nervous system side-effects

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People who switched single-tablet regimens from Atripla (efavirenz/tenofovir/emtricitabine) to Eviplera (rilpivirine/tenofovir/emtricitabine) maintained viral suppression and saw improvement in central nervous system (CNS) side-effects such as abnormal dreams and depression, according to a late-breaking poster presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this month in Denver. Two other studies looked at the safety and efficacy of Eviplera amongst women and black patients.

Atripla, a recommended first-line regimen in European and US antiretroviral treatment guidelines, is widely used, highly effective, convenient and generally considered safe and well tolerated. But many people taking efavirenz – an ingredient in the all-in-one pill – experience neuropsychiatric symptoms that may include insomnia, vivid dreams or nightmares, and depression or anxiety. 

Mark Nelson from the Chelsea and Westminster Hospital in London and colleagues evaluated outcomes amongst people with HIV who switched from Atripla to Eviplera, a similar once-daily single-tablet coformulation that substitutes a newer NNRTI, rilpivirine (sold separately as Edurant), for efavirenz. Eviplera is a recommended regimen in European guidelines and an 'alternative' in US guidelines.


central nervous system (CNS)

The brain and spinal cord. CNS side-effects refer to mood changes, anxiety, dizzyness, sleep disturbance, impact on mental health, etc.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.


A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).




A mental health problem causing long-lasting low mood that interferes with everyday life.

This phase 4 multicentre pilot study enrolled 40 people taking Atripla who had fully suppressed viral load but continued to be bothered by efavirenz-associated CNS side-effects after at least 12 weeks on treatment. All but four were men, the average age was 47 years and the median baseline CD4 T-cell count was high at 640 cells/mm3. They had been on efavirenz-based ART for a median of 40 months (range 4 to 165 months). 

The researchers assessed CNS toxicity at four and twelve weeks after the switch using ACTG adverse event scores and a 19-item sleep questionnaire, with scores converted to percentages. The CNS adverse events questionnaire asked about 10 symptoms – dizziness, depression, insomnia, anxiety or nervousness, confusion, impaired concentration, headache, somnolence or drowsiness, aggressive mood and abnormal dreams – each rated as absent, mild, moderate or severe.

The total CNS side-effects score declined significantly by four weeks after switching from Atripla to Eviplera, falling from a median of 40 to 12, with lower scores indicating fewer symptoms. By week 12 the median score rose somewhat, to 20, but was still a significant improvement over baseline. 

Scores for each individual symptom, except for headache, also showed significant improvement. The largest declines in the proportion of people experiencing moderate to severe (grade 2 to 4) symptoms were seen for abnormal dreams (about 75% at baseline to 10% at week 4), insomnia (60 to 20%), depression (just over 50% to just over 10%), somnolence (50% to about 12%) and impaired concentration (about 48% to under 10%). A few symptoms rebounded by more than 10% from week 4 to 12, but dizziness, aggressive mood and headache continued to decrease, whilst insomnia, confusion, somnolence and abnormal dreams remained fairly stable.

Total sleep scores also decreased significantly, from a median of 30 at baseline to 19 at week 4, and continued to fall to 16 at week 12, with lower scores again indicating improvement. 

All participants maintained viral suppression after switching to Eviplera. The median CD4 count fell to 584 cells/mm3 at week 12, but this was not a statistically significant change.

Blood lipids improved by week 12 after the switch, including significant declines in total cholesterol (-0.6mmol/l), LDL ('bad') cholesterol (-0.49mmol/l) and triglycerides (-0.28mmol/l). 

"Switching Atripla to Eviplera led to significant improvement" in CNS adverse events and sleep questionnaire scores with maintenance of virological suppression, the researchers concluded. "Identification of individuals with efavirenz toxicity is essential as alternative agents lead to improvements in toxicity profile and quality of life."

Eviplera in women

The open-label STaR trial compared the Eviplera and Atripla coformulations in people starting ART for the first time. Unlike the earlier ECHO and THRIVE trials, which compared the same drug combinations taken as separate pills plus placebos, both STaR arms took one pill once daily.

Researchers performed a sub-analysis of 56 women in the study, largely from the US south, who made up 7% of the total patient population (n=786). About two-thirds were white, one-quarter were black, the median age was 36 years and the mean baseline CD4 count was approximately 390 cells/mm3

Overall, both single-tablet regimens produced good viral suppression at 48 weeks, with 86% in the Eviplera arm and 82% in the Atripla arm achieving undetectable viral load (<50 copies/ml) in a 'snapshot' analysis, showing that Eviplera was non-inferior to Atripla.

Response rates were a bit lower for women in both arms and the difference between the regimens was greater, 79 vs 61% respectively. The difference was attributable to a lower rate of virological failure (7% vs 14%), less missing data and fewer early discontinuations due to adverse events (7 vs 11%) amongst women taking Eviplera

Women in the Eviplera arm reported fewer CNS side-effects (29 vs 36%), fewer psychiatric symptoms (7 vs 14%) and less skin rash (4 vs 25%) compared with Atripla recipients. Eviplera was associated with smaller increases in total and LDL cholesterol, but also HDL ('good') cholesterol.

"[Eviplera] has a better safety profile than [Atripla] in the female subpopulation," the researchers concluded, but added that the statistical power of this analysis was limited by the small number of women in each arm.

Switch from protease inhibitor

Finally, the open-label phase 3 SPIRIT study looked at outcomes amongst people with suppressed viral load on their first or second regimen who switched from a boosted protease inhibitor plus two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) to Eviplera.

At baseline about one-third each were taking atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra) whilst one-fifth were on darunavir (Prezista); most also used tenofovir/emtricitabine (Truvada). Participants were randomly assigned to switch to Eviplera either immediately or after six months. 

The study included a total of 476 participants in the US. Nearly 90% were men, about three-quarters were white, the median age was just over 40 years and the mean CD4 count approached 600 cells/mm3. The researchers also did a sub-analysis of 83 black/African-American patients

Overall, Eviplera was again shown to be non-inferior, with 94% of participants who switched right away and 90% who stayed on a protease inhibitor regimen maintaining undetectable HIV RNA (<50 copies/ml) at 24 weeks. At 48 weeks, 89% in the immediate switch arm and 92% in the delayed switch arm had undetectable viral load. 

Amongst black participants, viral suppression rates were similar: 95 vs 91% at 24 weeks and 89 vs 95% at 48 weeks.

No one who stayed on their protease inhibitor discontinued due to adverse events compared with 2% in the immediate Eviplera switch arm and 4% in the delayed switch arm. Only one black patient discontinued Eviplera. Overall, 6% in the immediate switch group and 8% in the delayed switch group experienced grade 3 to 4 side effects, with no significant differences between black and white participants. 

"Rates of virologic suppression through 24 weeks after switching to [Eviplera] were non-inferior to remaining on [a boosted protease inhibitor + two NRTIs] regardless of race," the researchers concluded.

They added that switching to Eviplera led to improvement in fasting lipids and had minimal impact on estimated glomerular filtration rate (eGFR, a measure of kidney function) regardless of race.


Nelson M et al. Multicentre Open-label study of switching from Atripla to Eviplera for possible efavirenz associated CNS toxicity. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, abstract H-672b, 2013. View the abstract on the ICAAC website.

Brinson C et al. STaR: virologic outcomes and safety in ART-naive adult females for single-tablet regimen rilpivirine/emtricitabine/tenofovir DF compared to efavirenz/emtricitabine/tenofovir DF at week 48. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, abstract H-655, 2013. View the abstract on the ICAAC website

Mounzer K et al. SPIRIT: Simplifying to rilpivirine/emtricitabine/tenofovir DF single-tablet regimen from boosted protease inhibitor regimen maintains HIV suppression in the black subgroup. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, abstract H-656, 2013. View the abstract on the ICAAC website.