• ACTG 5097s: Impact of Efavirenz (EFV) on Neuropsychological Performance, Mood and Sleep Behavior in HIV-Positive Individuals (Oral 54)
  Authored by D.B. Clifford, S. Evans, Y. Yang, E. Acosta, K. Goodkin, R.M. Gulick
  

One of the most eagerly awaited studies from this conference was ACTG 5097s, a substudy of ACTG 5095. As covered in another report, which provides the A5095 trial results, A5095 is a phase III, randomized, double-blind, active-controlled comparison of three antiretroviral regimens: co-formulated abacavir (ABC, Ziagen) + AZT (zidovudine, Retrovir) + 3TC (lamivudine, Epivir) tablet (Trizivir), versus efavirenz (EFV, Sustiva, Stocrin) plus co-formulated AZT and 3TC tablet (Combivir), versus efavirenz plus Trizivir. The A5097s study was designed to evaluate for and characterize efavirenz-associated neurological symptoms in a controlled treatment initiation protocol.

The 303 patients enrolled in A5097, 200 of whom were on efavirenz, were randomly selected from the A5095 study patients. The patients randomized were well balanced regarding baseline characteristics. The patients had a battery of tests and assessments over the first 24 weeks of antiretroviral therapy. Included in the assessments were:

• Neuropsychological performance using Z-scores of Digit Symbol Substitution and Trailmaking A and B, (NPZ-3);

• Pittsburgh Sleep Quality Index (PSQI);

• Center for Epidemiologic Studies -- Depression (CES-D);

• Spielberger State-Trait Anxiety Inventory (STAI);

• Symptom questionnaire specifically designed to evaluate efavirenz-specific side effects; and

• Efavirenz serum levels.

The patients were tested at baseline, and then again at weeks one, four, 12 and 24 of therapy.

The investigators found no significant differences in changes in neuropsychological testing at any time point among the patients who received or did not receive efavirenz arms. The symptom questionnaire, which was specifically designed to detect potential efavirenz-related side effects, detected significant increases in neurological symptoms at week one (P<0.001), but not at weeks four, 12 or 24.

Similarly, the PSQI revealed more "bad dreams" at week one in the efavirenz-treated patients (P=0.038), but there was no difference between the groups at weeks four, 12 or 24. Notably, better global PSQI scores and "sleep quality" were found in the efavirenz-containing arm at week four, but again the significance of this finding disappeared by week 12. At no time point was there a significant difference between the patients who received or did not receive efavirenz regarding total depressed mood (CES-D) or anxiety (STAI), nor in the proportion of subjects with clinically significant anxiety or high levels of depressive symptoms. The investigators did note that there were some small negative significant correlations between efavirenz levels and NPZ3, but there was no correlation between efavirenz level and mood.

The authors conclude, "In a large active-controlled trial, early neurologic symptoms distinct from depression or anxiety were associated with [efavirenz] use, and resolved by week four. Improvement in neuropsychologic performance was comparable in [efavirenz] and non-[efavirenz] treated subjects."

So, these data, along with the data from A5095 (which showed that efavirenz-containing regimens outperformed Trizivir and that the switch rate of efavirenz to nevirapine [NVP, Viramune] was only 6 percent due to CNS and other side effects) support prior data that have indicated that the CNS side effects that occur with efavirenz are generally mild and short-term. Since many patients stop efavirenz during the first two to four weeks of therapy due to CNS side effects, most notably sleep disturbances and "bad dreams," this should encourage both clinicians and patients to work toward continuing therapy, since, for the vast majority of patients who do continue, the symptoms will resolve.