- Category: Neurocognitive Problems
- Published on Sunday, 22 September 2013 00:00
- Written by Liz Highleyman
People who switched single-tablet regimens from Atripla (efavirenz/tenofovir/emtricitabine) to Complera (rilpivirine/tenofovir/emtricitabine) maintained viral load 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. Other studies looked at the safety and efficacy of Complera among women and black patients.
Atripla, a recommended first-line regimen in U.S. and European 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-1 pill -- experience neuropsychiatric symptoms that may include insomnia, vivid dreams or nightmares, hallucinations, and depression or anxiety. A study published earlier this year found that efavirenz interacts with some of the same brain receptors as LSD and other recreational drugs.
Mark Nelson from Chelsea and Westminster Hospital in London and colleagues evaluated outcomes among people with HIV who switched from Atripla to Complera, a similar once-daily single-tablet coformulation that substitutes a newer NNRTI, rilpivirine (sold separately as Edurant), for efavirenz. Complera is listed as an "alternative" regimen in U.S. guidelines.
This Phase 4 multicenter 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 4 were men, the average age was 47 years, and the median baseline CD4 T-cell count was 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 4 and 12 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 investigators also looked at continued viral suppression, changes in CD4 cell counts, and changes in fasting blood lipid levels.
- The total CNS side effects score declined significantly within 4 weeks after switching from Atripla to Complera, 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 2-4) symptoms were seen for:
o Abnormal dreams: about 75% at baseline to 10% at week 4;
o Insomnia: 60% to 20%;
o Depression: just over 50% to just over 10%;
o Somnolence: 50% to about 12%;
o Impaired concentration: about 48% to under 10%.
- Depression, anxiety, and impaired concentration rebounded by more than 10% from week 4 to week 12.
- Dizziness, headache, and aggressive mood continued to decrease.
- 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 regimens.
- 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 (-0.6 mmol/L), LDL ("bad") cholesterol (-0.49 mmol/L), and triglycerides (-0.28mmol/L).
"Switching Atripla to Complera 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."
Complera in Women
The open-label STaR trial compared the Complera and Atripla coformulations in people starting ART for the first time. Unlike the ECHO and THRIVE trials, which compared the same drug combinations taken as separate pills plus placebos, both STaR arms took 1 pill once-daily.
Researchers performed a sub-analysis of 56 women in the study, largely from the southern U.S., 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 Complera arm and 82% in the Atripla arm achieving undetectable viral load (<50 copies/mL) in a "snapshot" analysis, showing that Complera 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%) among women taking Complera.
Women in the Complera 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. Complera was associated with smaller increases in total and LDL cholesterol, but also HDL ("good") cholesterol.
"[Complera] 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 among people with suppressed viral load on their first or second regimen who switched from a boosted protease inhibitor plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) to Complera.
At baseline about one-third each were taking atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra) while one-fifth were on darunavir (Prezista); most also used tenofovir/emtricitabine (the drugs in Truvada). Participants were randomly assigned to switch to Complera either immediately or after 6 months.
The study included a total of 476 participants in the U.S. 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, Complera was again shown to be non-inferior, with 94% of participants who switched right away and 90% who stayed on the 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.
Among 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 Complera switch arm and 4% in the delayed switch arm. Only 1 black patient discontinued Complera. Overall, 6% in the immediate switch group and 8% in the delayed switch group experienced grade 3-4 side effects, with no significant differences between black and white participants.
"Rates of virologic suppression through 24 weeks after switching to [Complera] were non-inferior to remaining on [a boosted protease inhibitor + 2 NRTIs] regardless of race," the researchers concluded.
They added that switching to Complera led to improvement in fasting lipids and had minimal impact on estimated glomerular filtration rate (eGFR, a measure of kidney function) regardless of race.
M Nelson, A Winston, L Waters, 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 (ICAAC 2013). Denver, September 10-13, 2013.Abstract H-672b.
C Brinson, S Segal-Maurer, I Brar, 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 (ICAAC 2013). Denver, September 10-13, 2013.Abstract H-655.
K Mounzer, F Palella, J Slim, 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 (ICAAC 2013). Denver, September 10-13, 2013.Abstract H-656.